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1
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Gu RF, Hronowski X, Shao Z, Gao B, Soucey K, Sun F, Tsai HH, Wei R. Dynamic Proteome Changes in Cuprizone-Induced Demyelination and Remyelination in the Mouse Brain. J Proteome Res 2025. [PMID: 40305778 DOI: 10.1021/acs.jproteome.4c01036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025]
Abstract
This study aimed to gain insights into the dynamic proteome changes and underlying molecular mechanisms of de/remyelination in a cuprizone model, a widely used preclinical model of multiple sclerosis (MS). Longitudinal sampling of control or cuprizone-treated mouse brains was executed at 6 time points over 6 weeks. Data analysis included 8489 quantified proteins. Differential proteomic and GO analyses revealed that 5.9% of the quantified proteome was altered, including reported and novel de/remyelination-relevant protein changes and underlying pathways. We found that oligodendrocyte proteins (Fa2h and Ugt8) were significantly changed during demyelination, suggesting that dysregulated sphingolipid metabolism in MS may stem from oligodendrocyte pathology. Importantly, we showed that the cholesterol biosynthesis pathway was the most enriched biological process in a subset of significantly changed proteins, where myelination was highly enriched. We further validated the changes in the cholesterol biosynthesis pathway through targeted GC-MS analysis of intermediate sterols, supporting the critical role of cholesterol biosynthesis in de/remyelination. Unexpectedly, changes of myelin-associated proteins, Mbp and Plp1, were minimal, while Ermn showed significant reduction tracking with demyelination, indicating that some myelin protein changes are more sensitive to demyelination. Together with a list of significantly altered proteins, the results of this study could benefit future remyelination research.
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Affiliation(s)
- Rong-Fang Gu
- Chemical Biology and Proteomics, Biogen, Cambridge, Massachusetts 02142, United States
| | - Xiaoping Hronowski
- Chemical Biology and Proteomics, Biogen, Cambridge, Massachusetts 02142, United States
| | - Zhaohui Shao
- Multiple Sclerosis Immunology Research, Biogen, Cambridge, Massachusetts 02142, United States
| | - Benbo Gao
- Chemical Biology and Proteomics, Biogen, Cambridge, Massachusetts 02142, United States
| | - Kayla Soucey
- Multiple Sclerosis Immunology Research, Biogen, Cambridge, Massachusetts 02142, United States
| | - Fangxu Sun
- Chemical Biology and Proteomics, Biogen, Cambridge, Massachusetts 02142, United States
| | - Hui-Hsin Tsai
- Multiple Sclerosis Clinical Development, Biogen, Cambridge, Massachusetts 02142, United States
| | - Ru Wei
- Chemical Biology and Proteomics, Biogen, Cambridge, Massachusetts 02142, United States
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2
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Theisen EK, Rivas-Serna IM, Lee RJ, Jay TR, Kunduri G, Nguyen TT, Mazurak V, Clandinin MT, Clandinin TR, Vaughen JP. Glia phagocytose neuronal sphingolipids to infiltrate developing synapses. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.14.648777. [PMID: 40313927 PMCID: PMC12045345 DOI: 10.1101/2025.04.14.648777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
The complex morphologies of mature neurons and glia emerge through profound rearrangements of cell membranes during development. Despite being integral components of these membranes, it is unclear whether lipids might actively sculpt these morphogenic processes. By analyzing lipid levels in the developing fruit fly brain, we discover dramatic increases in specific sphingolipids coinciding with neural circuit establishment. Disrupting this sphingolipid bolus via genetic perturbations of sphingolipid biosynthesis and catabolism leads to impaired glial autophagy. Remarkably, glia can obtain sphingolipid precursors needed for autophagy by phagocytosing neurons. These precursors are then converted into specific long-chain ceramide phosphoethanolamines (CPEs), invertebrate analogs of sphingomyelin. These lipids are essential for glia to arborize and infiltrate the brain, a critical step in circuit maturation that when disrupted leads to reduced synapse numbers. Taken together, our results demonstrate how spatiotemporal tuning of sphingolipid metabolism during development plays an instructive role in programming brain architecture. Highlights Brain sphingolipids (SLs) remodel to very long-chain species during circuit maturation Glial autophagy requires de novo SL biosynthesis coordinated across neurons and glia Glia evade a biosynthetic blockade by phagolysosomal salvage of neuronal SLsCeramide Phosphoethanolamine is critical for glial infiltration and synapse density.
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3
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Brinkmeier ML, Wang SQ, Pittman HA, Cheung LY, Prasov L. Myelin regulatory factor (MYRF) is a critical early regulator of retinal pigment epithelial development. PLoS Genet 2025; 21:e1011670. [PMID: 40233131 PMCID: PMC12052213 DOI: 10.1371/journal.pgen.1011670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 05/05/2025] [Accepted: 04/01/2025] [Indexed: 04/17/2025] Open
Abstract
Myelin regulatory factor (Myrf) is a critical transcription factor in early retinal and retinal pigment epithelial development, and human variants in MYRF are a cause for nanophthalmos. Single cell RNA sequencing (scRNAseq) was performed on Myrf conditional knockout mice (Rx > Cre Myrffl/fl) at 3 developmental timepoints. Myrf was expressed specifically in the RPE, and expression was abrogated in Rx > Cre Myrffl/fl eyes. scRNAseq analysis revealed a loss of RPE cells at all timepoints resulting from cell death. GO-term analysis in the RPE revealed downregulation of melanogenesis and anatomic structure morphogenesis pathways, which were supported by electron microscopy and histologic analysis. Novel structural target genes including Ermn and Upk3b, along with macular degeneration and inherited retinal disease genes were identified as downregulated, and a strong upregulation of TGFß/BMP signaling and effectors was observed. Regulon analysis placed Myrf downstream or parallel to Pax6 and Mitf and upstream of Sox10 in RPE differentiation. Together, these results suggest a strong role for MYRF in the RPE maturation by regulating melanogenesis, cell survival, and cell structure, in part acting through suppression of TGFß signaling and activation of Sox10.
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Affiliation(s)
- Michelle L. Brinkmeier
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Su Qing Wang
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Hannah A. Pittman
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Leonard Y. Cheung
- Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York, United States of America
| | - Lev Prasov
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America
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4
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Zhao X, Wang Y, Yi X. Proteomic evidence for seed odor modifying olfaction and spatial memory in a scatter-hoarding animal. Behav Brain Res 2025; 477:115282. [PMID: 39369826 DOI: 10.1016/j.bbr.2024.115282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 09/28/2024] [Accepted: 10/02/2024] [Indexed: 10/08/2024]
Abstract
Seed odor plays a crucial role in affecting the scatter-hoarding behavior of small rodents that rely on spatial memory and olfaction to cache and recover. However, evidence of how seed odor modifies olfaction function and spatial memory is still lacking. Here, we coated seeds with waterproof glue to test how seed odor intensity alters the proteome of both the olfactory bulbs and hippocampus of a dominant scatter-hoarding rodent, Leopoldamys edwardsi, in Southwest China. We showed that animals repeatedly caching and recovering weak odor seeds exhibited greater olfactory ability and spatial memory, as indicated by alterations in the protein profiles of the olfactory bulbs and hippocampus. The upregulation of proteins closely related to neural connections between the olfactory bulb and hippocampus is highly responsible for improved olfactory function and spatial memory. Our study provides new insights into how scatter-hoarding rodents manage and respond to cached seeds differing in odor intensity from a neurobiological perspective, which is of significant importance for better understanding the parallel evolution of the olfactory and hippocampal systems.
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Affiliation(s)
- Xiangyu Zhao
- School of Life Sciences, Qufu Normal University, Qufu 273165, China
| | - Yingnan Wang
- School of Life Sciences, Qufu Normal University, Qufu 273165, China
| | - Xianfeng Yi
- School of Life Sciences, Qufu Normal University, Qufu 273165, China.
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5
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Lerma-Martin C, Badia-I-Mompel P, Ramirez Flores RO, Sekol P, Schäfer PSL, Riedl CJ, Hofmann A, Thäwel T, Wünnemann F, Ibarra-Arellano MA, Trobisch T, Eisele P, Schapiro D, Haeussler M, Hametner S, Saez-Rodriguez J, Schirmer L. Cell type mapping reveals tissue niches and interactions in subcortical multiple sclerosis lesions. Nat Neurosci 2024; 27:2354-2365. [PMID: 39501036 PMCID: PMC11614744 DOI: 10.1038/s41593-024-01796-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 09/30/2024] [Indexed: 11/08/2024]
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Inflammation is gradually compartmentalized and restricted to specific tissue niches such as the lesion rim. However, the precise cell type composition of such niches, their interactions and changes between chronic active and inactive stages are incompletely understood. We used single-nucleus and spatial transcriptomics from subcortical MS and corresponding control tissues to map cell types and associated pathways to lesion and nonlesion areas. We identified niches such as perivascular spaces, the inflamed lesion rim or the lesion core that are associated with the glial scar and a cilia-forming astrocyte subtype. Focusing on the inflamed rim of chronic active lesions, we uncovered cell-cell communication events between myeloid, endothelial and glial cell types. Our results provide insight into the cellular composition, multicellular programs and intercellular communication in tissue niches along the conversion from a homeostatic to a dysfunctional state underlying lesion progression in MS.
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Affiliation(s)
- Celia Lerma-Martin
- Department of Neurology, Division of Neuroimmunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Pau Badia-I-Mompel
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany
- GSK, Cellzome, Heidelberg, Germany
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK
| | - Ricardo O Ramirez Flores
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK
| | - Patricia Sekol
- Department of Neurology, Division of Neuroimmunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philipp S L Schäfer
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK
| | - Christian J Riedl
- Department of Neurology, Division of Neuropathology and Neurochemistry, Medical University of Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria
| | - Annika Hofmann
- Department of Neurology, Division of Neuroimmunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Thomas Thäwel
- Department of Neurology, Division of Neuroimmunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Florian Wünnemann
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany
| | - Miguel A Ibarra-Arellano
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany
| | - Tim Trobisch
- Department of Neurology, Division of Neuroimmunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philipp Eisele
- Department of Neurology, Division of Neuroimmunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Center for Translational Neuroscience, Medical Faculty, Mannheim Heidelberg University, Mannheim, Germany
| | - Denis Schapiro
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany
- Institute of Pathology, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany
- Translational Spatial Profiling Center (TSPC), Heidelberg, Germany
| | | | - Simon Hametner
- Department of Neurology, Division of Neuropathology and Neurochemistry, Medical University of Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria
| | - Julio Saez-Rodriguez
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany.
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
| | - Lucas Schirmer
- Department of Neurology, Division of Neuroimmunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Mannheim Center for Translational Neuroscience, Medical Faculty, Mannheim Heidelberg University, Mannheim, Germany.
- Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany.
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6
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Srivastava A, Rajput P, Tripathi M, Chandra PS, Doddamani R, Sharma MC, Lalwani S, Banerjee J, Dixit AB. Integrated Proteomics and Protein Co-expression Network Analysis Identifies Novel Epileptogenic Mechanism in Mesial Temporal Lobe Epilepsy. Mol Neurobiol 2024; 61:9663-9679. [PMID: 38687446 DOI: 10.1007/s12035-024-04186-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 03/12/2024] [Indexed: 05/02/2024]
Abstract
Over 50 million people worldwide are affected by epilepsy, a common neurological disorder that has a high rate of drug resistance and diverse comorbidities such as progressive cognitive and behavioural disorders, and increased mortality from direct or indirect effects of seizures and therapies. Despite extensive research with animal models and human studies, limited insights have been gained into the mechanisms underlying seizures and epileptogenesis, which has not translated into significant reductions in drug resistance, morbidities, or mortality. To better understand the molecular signaling networks associated with seizures in MTLE patients, we analyzed the proteome of brain samples from MTLE and control cases using an integrated approach that combines mass spectrometry-based quantitative proteomics, differential expression analysis, and co-expression network analysis. Our analyses of 20 human brain tissues from MTLE patients and 20 controls showed the organization of the brain proteome into a network of 9 biologically meaningful modules of co-expressed proteins. Of these, 6 modules are positively or negatively correlated to MTLE phenotypes with hub proteins that are altered in MTLE patients. Our study is the first to employ an integrated approach of proteomics and protein co-expression network analysis to study patients with MTLE. Our findings reveal a molecular blueprint of altered protein networks in MTLE brain and highlight dysregulated pathways and processes including altered cargo transport, neurotransmitter release from synaptic vesicles, synaptic plasticity, proteostasis, RNA homeostasis, ion transport and transmembrane transport, cytoskeleton disorganization, metabolic and mitochondrial dysfunction, blood micro-particle function, extracellular matrix organization, immune response, neuroinflammation, and cell signaling. These insights into MTLE pathogenesis suggest potential new candidates for future diagnostic and therapeutic development.
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Affiliation(s)
| | - Priya Rajput
- Dr B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India
| | | | | | | | | | - Sanjeev Lalwani
- Department of Forensic Medicine & Toxicology, AIIMS, New Delhi, India
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7
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Stassen SV, Kobashi M, Lam EY, Huang Y, Ho JWK, Tsia KK. StaVia: spatially and temporally aware cartography with higher-order random walks for cell atlases. Genome Biol 2024; 25:224. [PMID: 39152459 PMCID: PMC11328412 DOI: 10.1186/s13059-024-03347-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 07/23/2024] [Indexed: 08/19/2024] Open
Abstract
Single-cell atlases pose daunting computational challenges pertaining to the integration of spatial and temporal information and the visualization of trajectories across large atlases. We introduce StaVia, a computational framework that synergizes multi-faceted single-cell data with higher-order random walks that leverage the memory of cells' past states, fused with a cartographic Atlas View that offers intuitive graph visualization. This spatially aware cartography captures relationships between cell populations based on their spatial location as well as their gene expression and developmental stage. We demonstrate this using zebrafish gastrulation data, underscoring its potential to dissect complex biological landscapes in both spatial and temporal contexts.
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Affiliation(s)
- Shobana V Stassen
- Department of Electrical and Electronic Engineering, The University of Hong Kong, Pokfulam, Hong Kong, Hong Kong.
| | - Minato Kobashi
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Edmund Y Lam
- Department of Electrical and Electronic Engineering, The University of Hong Kong, Pokfulam, Hong Kong, Hong Kong
- AI Chip Center for Emerging Smart Systems, Hong Kong Science Park, Shatin, New Territories, Hong Kong
| | - Yuanhua Huang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
- Department of Statistics and Actuarial Science, The University of Hong Kong, Pokfulam, Hong Kong
| | - Joshua W K Ho
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
- Laboratory of Data Discovery for Health, Hong Kong Science Park, Shatin, New Territories, Hong Kong
| | - Kevin K Tsia
- Department of Electrical and Electronic Engineering, The University of Hong Kong, Pokfulam, Hong Kong, Hong Kong.
- Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, New Territories, Hong Kong.
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8
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Zhang T, Liu X, Rossio V, Dawson SL, Gygi SP, Paulo JA. Enhancing Proteome Coverage by Using Strong Anion-Exchange in Tandem with Basic-pH Reversed-Phase Chromatography for Sample Multiplexing-Based Proteomics. J Proteome Res 2024; 23:2870-2881. [PMID: 37962907 PMCID: PMC11090996 DOI: 10.1021/acs.jproteome.3c00492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Sample multiplexing-based proteomic strategies rely on fractionation to improve proteome coverage. Tandem mass tag (TMT) experiments, for example, can currently accommodate up to 18 samples with proteins spanning several orders of magnitude, thus necessitating fractionation to achieve reasonable proteome coverage. Here, we present a simple yet effective peptide fractionation strategy that partitions a pooled TMT sample with a two-step elution using a strong anion-exchange (SAX) spin column prior to gradient-based basic pH reversed-phase (BPRP) fractionation. We highlight our strategy with a TMTpro18-plex experiment using nine diverse human cell lines in biological duplicate. We collected three data sets, one using only BPRP fractionation and two others of each SAX-partition followed by BPRP. The three data sets quantified a similar number of proteins and peptides, and the data highlight noticeable differences in the distribution of peptide charge and isoelectric point between the SAX partitions. The combined SAX partition data set contributed 10% more proteins and 20% more unique peptides that were not quantified by BPRP fractionation alone. In addition to this improved fractionation strategy, we provide an online resource of relative abundance profiles for over 11,000 proteins across the nine human cell lines, as well as two additional experiments using ovarian and pancreatic cancer cell lines.
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Affiliation(s)
- Tian Zhang
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Xinyue Liu
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Valentina Rossio
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Shane L Dawson
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Steven P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Joao A Paulo
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
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9
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Hang WX, Yang YC, Hu YH, Fang FQ, Wang L, Qian XH, Mcquillan PM, Xiong H, Leng JH, Hu ZY. General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain. Zool Res 2024; 45:691-703. [PMID: 38766750 PMCID: PMC11188601 DOI: 10.24272/j.issn.2095-8137.2023.413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 04/01/2024] [Indexed: 05/22/2024] Open
Abstract
General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells. Oligodendrocytes perform essential roles in the central nervous system, including myelin sheath formation, axonal metabolism, and neuroplasticity regulation. They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation, differentiation, and apoptosis. Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes. These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways, but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function. In this review, we summarize the effects of general anesthetic agents on oligodendrocytes. We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.
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Affiliation(s)
- Wen-Xin Hang
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Yan-Chang Yang
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Yu-Han Hu
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA
| | - Fu-Quan Fang
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Lang Wang
- Department of Neurology of the First Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310027, China
| | - Xing-Hua Qian
- Department of Anesthesiology, Jiaxing Maternity and Childcare Health Hospital, Jiaxing, Zhejiang 314009, China
| | - Patrick M Mcquillan
- Department of Anesthesiology, Penn State Hershey Medical Centre, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Hui Xiong
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Jian-Hang Leng
- Department of Central Laboratory, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang 310006, China. E-mail:
| | - Zhi-Yong Hu
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China. E-mail:
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10
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Caban KM, Seßenhausen P, Stöckl JB, Popper B, Mayerhofer A, Fröhlich T. Proteome profile of the cerebellum from α7 nicotinic acetylcholine receptor deficient mice. Proteomics 2024; 24:e2300384. [PMID: 38185761 DOI: 10.1002/pmic.202300384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/18/2023] [Accepted: 12/19/2023] [Indexed: 01/09/2024]
Abstract
The alpha7 nicotinic acetylcholine receptor (α7 nAChR; CHRNA7) is expressed in the nervous system and in non-neuronal tissues. Within the central nervous system, it is involved in various cognitive and sensory processes such as learning, attention, and memory. It is also expressed in the cerebellum, where its roles are; however, not as well understood as in the other brain regions. To investigate the consequences of absence of CHRNA7 on the cerebellum proteome, we performed a quantitative nano-LC-MS/MS analysis of samples from CHRNA7 knockout (KO) mice and corresponding wild type (WT) controls. Liver, an organ which does not express this receptor, was analyzed, in comparison. While the liver proteome remained relatively unaltered (three proteins more abundant in KOs), 90 more and 20 less abundant proteins were detected in the cerebellum proteome of the KO mice. The gene ontology analysis of the differentially abundant proteins indicates that the absence of CHRNA7 leads to alterations in the glutamatergic system and myelin sheath in the cerebellum. In conclusion, our dataset provides new insights in the role of CHRNA7 in the cerebellum, which may serve as a basis for future in depth-investigations.
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Affiliation(s)
| | - Pia Seßenhausen
- Biomedical Center Munich (BMC), Cell Biology, Anatomy III, Faculty of Medicine, Ludwig Maximilian University of Munich, Planegg-Martinsried, Germany
| | - Jan Bernard Stöckl
- Laboratory for Functional Genome Analysis LAFUGA, Gene Center, LMU München, München, Germany
| | - Bastian Popper
- Biomedical Center (BMC), Core Facility Animal Models, Faculty of Medicine, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany
| | - Artur Mayerhofer
- Biomedical Center Munich (BMC), Cell Biology, Anatomy III, Faculty of Medicine, Ludwig Maximilian University of Munich, Planegg-Martinsried, Germany
| | - Thomas Fröhlich
- Laboratory for Functional Genome Analysis LAFUGA, Gene Center, LMU München, München, Germany
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11
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Brinkmeier ML, Wang SQ, Pittman H, Cheung LY, Prasov L. Myelin regulatory factor ( Myrf ) is a critical early regulator of retinal pigment epithelial development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.26.591281. [PMID: 38746430 PMCID: PMC11092522 DOI: 10.1101/2024.04.26.591281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Myelin regulatory factor (Myrf) is a critical transcription factor in early retinal and retinal pigment epithelial development, and human variants in MYRF are a cause for nanophthalmos. Single cell RNA sequencing (scRNAseq) was performed on Myrf conditional knockout mice ( Rx>Cre Myrf fl/fl ) at 3 developmental timepoints. Myrf was expressed specifically in the RPE, and expression was abrogated in Rx>Cre Myrf fl/fl eyes. scRNAseq analysis revealed a loss of RPE cells at all timepoints resulting from cell death. GO-term analysis in the RPE revealed downregulation of melanogenesis and anatomic structure morphogenesis pathways, which were supported by electron microscopy and histologic analysis. Novel structural target genes including Ermn and Upk3b , along with macular degeneration and inherited retinal disease genes were identified as downregulated, and a strong upregulation of TGFß/BMP signaling and effectors was observed. Regulon analysis placed Myrf downstream of Pax6 and Mitf and upstream of Sox10 in RPE differentiation. Together, these results suggest a strong role for Myrf in the RPE maturation by regulating melanogenesis, cell survival, and cell structure, in part acting through suppression of TGFß signaling and activation of Sox10 . SUMMARY STATEMENT Myrf regulates RPE development, melanogenesis, and is important for cell structure and survival, in part through regulation of Ermn , Upk3b and Sox10, and BMP/TGFb signaling.
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12
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Roy B, Pekec T, Yuan L, Shivashankar GV. Implanting mechanically reprogrammed fibroblasts for aged tissue regeneration and wound healing. Aging Cell 2024; 23:e14032. [PMID: 38010905 PMCID: PMC10861198 DOI: 10.1111/acel.14032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 08/22/2023] [Accepted: 10/05/2023] [Indexed: 11/29/2023] Open
Abstract
Cell-based therapies are essential for tissue regeneration and wound healing during aging. Autologous transplantation of aging cells is ineffective due to their increased senescence and reduced tissue remodeling capabilities. Alternatively, implanting reprogrammed aged cells provides unique opportunities. In this paper, we demonstrate the implantation of partially reprogrammed aged human dermal fibroblasts into in vitro aged skin models for tissue regeneration and wound healing. The partially reprogrammed cells were obtained using our previously reported, highly efficient mechanical approach. Implanted cells showed enhanced expression of extracellular matrix proteins in the large area of aged tissue. In addition, the implanted cells at wound sites showed increased extracellular matrix protein synthesis and matrix alignment. Transcriptome analysis, combined with chromatin biomarkers, revealed these implanted cells upregulated tissue regeneration and wound healing pathways. Collectively our results provide a novel, nongenetic, partial reprogramming of aged cells for cell-based therapies in regenerative medicine.
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Affiliation(s)
- Bibhas Roy
- Division of Biology and ChemistryPaul Scherrer InstituteVilligenSwitzerland
| | - Tina Pekec
- Division of Biology and ChemistryPaul Scherrer InstituteVilligenSwitzerland
| | - Luezhen Yuan
- Division of Biology and ChemistryPaul Scherrer InstituteVilligenSwitzerland
- Department of Health Sciences and TechnologyETH ZurichZurichSwitzerland
| | - G. V. Shivashankar
- Division of Biology and ChemistryPaul Scherrer InstituteVilligenSwitzerland
- Department of Health Sciences and TechnologyETH ZurichZurichSwitzerland
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13
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Morrissey ZD, Gao J, Shetti A, Li W, Zhan L, Li W, Fortel I, Saido T, Saito T, Ajilore O, Cologna SM, Lazarov O, Leow AD. Temporal Alterations in White Matter in An App Knock-In Mouse Model of Alzheimer's Disease. eNeuro 2024; 11:ENEURO.0496-23.2024. [PMID: 38290851 PMCID: PMC10897532 DOI: 10.1523/eneuro.0496-23.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/05/2024] [Accepted: 01/17/2024] [Indexed: 02/01/2024] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia and results in neurodegeneration and cognitive impairment. White matter (WM) is affected in AD and has implications for neural circuitry and cognitive function. The trajectory of these changes across age, however, is still not well understood, especially at earlier stages in life. To address this, we used the AppNL-G-F/NL-G-F knock-in (APPKI) mouse model that harbors a single copy knock-in of the human amyloid precursor protein (APP) gene with three familial AD mutations. We performed in vivo diffusion tensor imaging (DTI) to study how the structural properties of the brain change across age in the context of AD. In late age APPKI mice, we observed reduced fractional anisotropy (FA), a proxy of WM integrity, in multiple brain regions, including the hippocampus, anterior commissure (AC), neocortex, and hypothalamus. At the cellular level, we observed greater numbers of oligodendrocytes in middle age (prior to observations in DTI) in both the AC, a major interhemispheric WM tract, and the hippocampus, which is involved in memory and heavily affected in AD, prior to observations in DTI. Proteomics analysis of the hippocampus also revealed altered expression of oligodendrocyte-related proteins with age and in APPKI mice. Together, these results help to improve our understanding of the development of AD pathology with age, and imply that middle age may be an important temporal window for potential therapeutic intervention.
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Affiliation(s)
- Zachery D Morrissey
- Graduate Program in Neuroscience, University of Illinois Chicago, Chicago, Illinois 60612
- Department of Psychiatry, University of Illinois Chicago, Chicago, Illinois 60612
- Department of Anatomy & Cell Biology, University of Illinois Chicago, Chicago, Illinois 60612
| | - Jin Gao
- Department of Electrical & Computer Engineering, University of Illinois Chicago, Chicago, Illinois 60607
- Preclinical Imaging Core, University of Illinois Chicago, Chicago, Illinois 60612
| | - Aashutosh Shetti
- Department of Anatomy & Cell Biology, University of Illinois Chicago, Chicago, Illinois 60612
| | - Wenping Li
- Department of Chemistry, University of Illinois Chicago, Chicago, Illinois 60607
| | - Liang Zhan
- Department of Electrical & Computer Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
| | - Weiguo Li
- Preclinical Imaging Core, University of Illinois Chicago, Chicago, Illinois 60612
- Department of Bioengineering, University of Illinois Chicago, Chicago, Illinois 60607
- Department of Radiology, Northwestern University, Chicago, Illinois 60611
| | - Igor Fortel
- Department of Bioengineering, University of Illinois Chicago, Chicago, Illinois 60607
| | - Takaomi Saido
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako 351-0198, Japan
| | - Takashi Saito
- Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University, Nagoya 467-8601, Japan
| | - Olusola Ajilore
- Department of Psychiatry, University of Illinois Chicago, Chicago, Illinois 60612
| | - Stephanie M Cologna
- Department of Chemistry, University of Illinois Chicago, Chicago, Illinois 60607
| | - Orly Lazarov
- Department of Anatomy & Cell Biology, University of Illinois Chicago, Chicago, Illinois 60612
| | - Alex D Leow
- Department of Psychiatry, University of Illinois Chicago, Chicago, Illinois 60612
- Department of Bioengineering, University of Illinois Chicago, Chicago, Illinois 60607
- Department of Computer Science, University of Illinois Chicago, Chicago, Illinois 60607
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14
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Ferrari Bardile C, Radulescu CI, Pouladi MA. Oligodendrocyte pathology in Huntington's disease: from mechanisms to therapeutics. Trends Mol Med 2023; 29:802-816. [PMID: 37591764 DOI: 10.1016/j.molmed.2023.07.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/18/2023] [Accepted: 07/20/2023] [Indexed: 08/19/2023]
Abstract
Oligodendrocytes (OLGs), highly specialized glial cells that wrap axons with myelin sheaths, are critical for brain development and function. There is new recognition of the role of OLGs in the pathogenesis of neurodegenerative diseases (NDDs), including Huntington's disease (HD), a prototypic NDD caused by a polyglutamine tract expansion in huntingtin (HTT), which results in gain- and loss-of-function effects. Clinically, HD is characterized by a constellation of motor, cognitive, and psychiatric disturbances. White matter (WM) structures, representing myelin-rich regions of the brain, are profoundly affected in HD, and recent findings reveal oligodendroglia dysfunction as an early pathological event. Here, we focus on mechanisms that underlie oligodendroglial deficits and dysmyelination in the progression of the disease, highlighting the pathogenic contributions of mutant HTT (mHTT). We also discuss potential therapeutic implications involving these molecular pathways.
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Affiliation(s)
- Costanza Ferrari Bardile
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Djavad Mowafaghian Centre for Brain Health, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
| | - Carola I Radulescu
- UK Dementia Research Institute, Imperial College London, London, W12 0NN, UK
| | - Mahmoud A Pouladi
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Djavad Mowafaghian Centre for Brain Health, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
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15
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Martins S, Coletti R, Lopes MB. Disclosing transcriptomics network-based signatures of glioma heterogeneity using sparse methods. BioData Min 2023; 16:26. [PMID: 37752578 PMCID: PMC10523751 DOI: 10.1186/s13040-023-00341-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 08/13/2023] [Indexed: 09/28/2023] Open
Abstract
Gliomas are primary malignant brain tumors with poor survival and high resistance to available treatments. Improving the molecular understanding of glioma and disclosing novel biomarkers of tumor development and progression could help to find novel targeted therapies for this type of cancer. Public databases such as The Cancer Genome Atlas (TCGA) provide an invaluable source of molecular information on cancer tissues. Machine learning tools show promise in dealing with the high dimension of omics data and extracting relevant information from it. In this work, network inference and clustering methods, namely Joint Graphical lasso and Robust Sparse K-means Clustering, were applied to RNA-sequencing data from TCGA glioma patients to identify shared and distinct gene networks among different types of glioma (glioblastoma, astrocytoma, and oligodendroglioma) and disclose new patient groups and the relevant genes behind groups' separation. The results obtained suggest that astrocytoma and oligodendroglioma have more similarities compared with glioblastoma, highlighting the molecular differences between glioblastoma and the others glioma subtypes. After a comprehensive literature search on the relevant genes pointed our from our analysis, we identified potential candidates for biomarkers of glioma. Further molecular validation of these genes is encouraged to understand their potential role in diagnosis and in the design of novel therapies.
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Affiliation(s)
- Sofia Martins
- NOVA School of Science and Technology, NOVA University of Lisbon, Caparica, 2829-516, Portugal
| | - Roberta Coletti
- Center for Mathematics and Applications (NOVA Math), NOVA School of Science and Technology, Caparica, 2829-516, Portugal.
| | - Marta B Lopes
- NOVA School of Science and Technology, NOVA University of Lisbon, Caparica, 2829-516, Portugal.
- Center for Mathematics and Applications (NOVA Math), NOVA School of Science and Technology, Caparica, 2829-516, Portugal.
- NOVA Laboratory for Computer Science and Informatics (NOVA LINCS), NOVA School of Science and Technology, Caparica, 2829-516, Portugal.
- UNIDEMI, Department of Mechanical and Industrial Engineering, NOVA School of Science and Technology, Caparica, 2829-516, Portugal.
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16
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Bregalda A, Carducci C, Viscomi MT, Pierigè F, Biagiotti S, Menotta M, Biancucci F, Pascucci T, Leuzzi V, Magnani M, Rossi L. Myelin basic protein recovery during PKU mice lifespan and the potential role of microRNAs on its regulation. Neurobiol Dis 2023; 180:106093. [PMID: 36948260 DOI: 10.1016/j.nbd.2023.106093] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 03/24/2023] Open
Abstract
Untreated phenylketonuria (PKU) patients and PKU animal models show hypomyelination in the central nervous system and white matter damages, which are accompanied by myelin basic protein (MBP) impairment. Despite many assumptions, the primary explanation of the mentioned cerebral outcomes remains elusive. In this study, MBP protein and mRNA expression on brains of wild type (WT) and phenylketonuric (ENU2) mice were analyzed throughout mice lifespan (14-60-180-270-360-540 post-natal days, PND). The results confirmed the low MBP expression at first PND times, while revealed an unprecedented progressive MBP protein expression recovery in aged ENU2 mice. Unexpectedly, unaltered MBP mRNA expression between WT and ENU2 was always observed. Additionally, for the same time intervals, a significant decrease of the phenylalanine concentration in the peripheral blood and brain of ENU2 mice was detected, to date, for the first time. In this scenario, a translational hindrance of MBP during initial and late cerebral development in ENU2 mice was hypothesized, leading to the execution of a microRNA microarray analysis on 60 PND brains, which was followed by a proteomic assay on 60 and 360 PND brains in order to validate in silico miRNA-target predictions. Taken together, miR-218 - 1-3p, miR - 1231-3p and miR-217-5p were considered as the most impactful microRNAs, since a downregulation of their potential targets (MAG, CNTNAP2 and ANLN, respectively) can indirectly lead to a low MBP protein expression. These miRNAs, in addition, follow an opposite expression trend compared to MBP during adulthood, and their target proteins revealed a complete normalization in aged ENU2 mice. In conclusion, these results provide a new perspective on the PKU pathophysiology understanding and on a possible treatment, emphasizing the potential modulating role of differentially expressed microRNAs in MBP expression on PKU brains during PKU mouse lifespan.
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Affiliation(s)
- Alessandro Bregalda
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", via Saffi 2, 61029 Urbino, PU, Italy.
| | - Claudia Carducci
- Department of Experimental Medicine, Sapienza University, viale del Policlinico 155, 00161 Rome, Italy
| | - Maria Teresa Viscomi
- Department of Life Sciences and Public Health, Sect. Histology and Embryology, Università Cattolica del S. Cuore, Largo F. Vito 1, 00168 Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli", IRCCS, 00168 Rome, Italy
| | - Francesca Pierigè
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", via Saffi 2, 61029 Urbino, PU, Italy
| | - Sara Biagiotti
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", via Saffi 2, 61029 Urbino, PU, Italy
| | - Michele Menotta
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", via Saffi 2, 61029 Urbino, PU, Italy
| | - Federica Biancucci
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", via Saffi 2, 61029 Urbino, PU, Italy
| | - Tiziana Pascucci
- Fondazione Santa Lucia IRCCS, via Ardeatina 306, 00142 Rome, Italy; Department of Psychology and Centro "Daniel Bovet", Sapienza University, via dei Marsi 78, 00185 Rome, Italy
| | - Vincenzo Leuzzi
- Department of Human Neuroscience, Sapienza University, via dei Sabelli 108, 00185 Rome, Italy
| | - Mauro Magnani
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", via Saffi 2, 61029 Urbino, PU, Italy; EryDel SpA, via Antonio Meucci 3, 20091 Bresso, Milan, Italy
| | - Luigia Rossi
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", via Saffi 2, 61029 Urbino, PU, Italy; EryDel SpA, via Antonio Meucci 3, 20091 Bresso, Milan, Italy
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17
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Heo D, Ling JP, Molina-Castro GC, Langseth AJ, Waisman A, Nave KA, Möbius W, Wong PC, Bergles DE. Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43. eLife 2022; 11:e75230. [PMID: 35311646 PMCID: PMC8970587 DOI: 10.7554/elife.75230] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 03/18/2022] [Indexed: 12/12/2022] Open
Abstract
Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA-binding protein, TDP-43, occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures, and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43-deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced, leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult central nervous system (CNS) induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease.
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Affiliation(s)
- Dongeun Heo
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Jonathan P Ling
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Gian C Molina-Castro
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Abraham J Langseth
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Klaus-Armin Nave
- Department of Neurogenetics, Max Planck Institute of Experimental MedicineGöttingenGermany
| | - Wiebke Möbius
- Department of Neurogenetics, Max Planck Institute of Experimental MedicineGöttingenGermany
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of GöttingenGöttingenGermany
- Electron Microscopy Core Unit, Max-Planck-Institute of Experimental MedicineGöttingenGermany
| | - Phil C Wong
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Dwight E Bergles
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineBaltimoreUnited States
- Kavli Neuroscience Discovery Institute, Johns Hopkins UniversityBaltimoreUnited States
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18
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Ziaei A, Garcia-Miralles M, Radulescu CI, Sidik H, Silvin A, Bae HG, Bonnard C, Yusof NABM, Ferrari Bardile C, Tan LJ, Ng AYJ, Tohari S, Dehghani L, Henry L, Yeo XY, Lee S, Venkatesh B, Langley SR, Shaygannejad V, Reversade B, Jung S, Ginhoux F, Pouladi MA. Ermin deficiency leads to compromised myelin, inflammatory milieu, and susceptibility to demyelinating insult. Brain Pathol 2022; 32:e13064. [PMID: 35285112 PMCID: PMC9425013 DOI: 10.1111/bpa.13064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 01/09/2022] [Accepted: 02/10/2022] [Indexed: 11/28/2022] Open
Abstract
Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here, we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near-exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling "inside-out" model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies.
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Affiliation(s)
- Amin Ziaei
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.,UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA
| | - Marta Garcia-Miralles
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Carola I Radulescu
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Harwin Sidik
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Aymeric Silvin
- Singapore Immunology Network (SIgN), A*STAR, Singapore, Singapore
| | - Han-Gyu Bae
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore.,Department of Life Sciences, Yeungnam University, Gyeongsan, South Korea
| | - Carine Bonnard
- Institute of Medical Biology, A*STAR, Singapore, Singapore
| | - Nur Amirah Binte Mohammad Yusof
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Costanza Ferrari Bardile
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.,Department of Medical Genetics, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Liang Juin Tan
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Alvin Yu Jin Ng
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore
| | - Sumanty Tohari
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore
| | - Leila Dehghani
- Department of Neurology, Isfahan Neurosciences Research Centre, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Lily Henry
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Xin Yi Yeo
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore
| | - Sejin Lee
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore
| | - Byrappa Venkatesh
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore.,Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Sarah R Langley
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Vahid Shaygannejad
- Department of Neurology, Isfahan Neurosciences Research Centre, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Sangyong Jung
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore.,Department of Physiology, National University of Singapore, Singapore, Singapore
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), A*STAR, Singapore, Singapore.,Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Mahmoud A Pouladi
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.,Department of Medical Genetics, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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19
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Valdés-Tovar M, Rodríguez-Ramírez AM, Rodríguez-Cárdenas L, Sotelo-Ramírez CE, Camarena B, Sanabrais-Jiménez MA, Solís-Chagoyán H, Argueta J, López-Riquelme GO. Insights into myelin dysfunction in schizophrenia and bipolar disorder. World J Psychiatry 2022; 12:264-285. [PMID: 35317338 PMCID: PMC8900585 DOI: 10.5498/wjp.v12.i2.264] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/10/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia and bipolar disorder are disabling psychiatric disorders with a worldwide prevalence of approximately 1%. Both disorders present chronic and deteriorating prognoses that impose a large burden, not only on patients but also on society and health systems. These mental illnesses share several clinical and neurobiological traits; of these traits, oligodendroglial dysfunction and alterations to white matter (WM) tracts could underlie the disconnection between brain regions related to their symptomatic domains. WM is mainly composed of heavily myelinated axons and glial cells. Myelin internodes are discrete axon-wrapping membrane sheaths formed by oligodendrocyte processes. Myelin ensheathment allows fast and efficient conduction of nerve impulses through the nodes of Ranvier, improving the overall function of neuronal circuits. Rapid and precisely synchronized nerve impulse conduction through fibers that connect distant brain structures is crucial for higher-level functions, such as cognition, memory, mood, and language. Several cellular and subcellular anomalies related to myelin and oligodendrocytes have been found in postmortem samples from patients with schizophrenia or bipolar disorder, and neuroimaging techniques have revealed consistent alterations at the macroscale connectomic level in both disorders. In this work, evidence regarding these multilevel alterations in oligodendrocytes and myelinated tracts is discussed, and the involvement of proteins in key functions of the oligodendroglial lineage, such as oligodendrogenesis and myelination, is highlighted. The molecular components of the axo-myelin unit could be important targets for novel therapeutic approaches to schizophrenia and bipolar disorder.
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Affiliation(s)
- Marcela Valdés-Tovar
- Departamento de Farmacogenética, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | | | - Leslye Rodríguez-Cárdenas
- Departamento de Farmacogenética, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | - Carlo E Sotelo-Ramírez
- Departamento de Farmacogenética, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
- Doctorado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico
| | - Beatriz Camarena
- Departamento de Farmacogenética, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | | | - Héctor Solís-Chagoyán
- Laboratorio de Neurofarmacología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | - Jesús Argueta
- Doctorado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico
- Laboratorio de Neurofarmacología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | - Germán Octavio López-Riquelme
- Laboratorio de Socioneurobiología, Centro de Investigación en Ciencias Cognitivas, Universidad del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico
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20
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Edgar JM, McGowan E, Chapple KJ, Möbius W, Lemgruber L, Insall RH, Nave K, Boullerne A. Río-Hortega's drawings revisited with fluorescent protein defines a cytoplasm-filled channel system of CNS myelin. J Anat 2021; 239:1241-1255. [PMID: 34713444 PMCID: PMC8602028 DOI: 10.1111/joa.13577] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/10/2021] [Accepted: 10/11/2021] [Indexed: 01/13/2023] Open
Abstract
A century ago this year, Pío del Río-Hortega (1921) coined the term 'oligodendroglia' for the 'interfascicular glia' with very few processes, launching an extensive discovery effort on his new cell type. One hundred years later, we review his original contributions to our understanding of the system of cytoplasmic channels within myelin in the context of what we observe today using light and electron microscopy of genetically encoded fluorescent reporters and immunostaining. We use the term myelinic channel system to describe the cytoplasm-delimited spaces associated with myelin; being the paranodal loops, inner and outer tongues, cytoplasm-filled spaces through compact myelin and further complex motifs associated to the sheath. Using a central nervous system myelinating cell culture model that contains all major neural cell types and produces compact myelin, we find that td-tomato fluorescent protein delineates the myelinic channel system in a manner reminiscent of the drawings of adult white matter by Río-Hortega, despite that he questioned whether some cytoplasmic figures he observed represented artefact. Together, these data lead us to propose a slightly revised model of the 'unrolled' sheath. Further, we show that the myelinic channel system, while relatively stable, can undergo subtle dynamic shape changes over days. Importantly, we capture an under-appreciated complexity of the myelinic channel system in mature myelin sheaths.
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Affiliation(s)
- Julia M. Edgar
- Axo‐Glial GroupInstitute of Infection, Immunity and InflammationCollege of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
- Department of NeurogeneticsMax Planck Institute of Experimental MedicineGöttingenGermany
| | - Eleanor McGowan
- Axo‐Glial GroupInstitute of Infection, Immunity and InflammationCollege of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
| | - Katie J. Chapple
- Axo‐Glial GroupInstitute of Infection, Immunity and InflammationCollege of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
| | - Wiebke Möbius
- Department of NeurogeneticsMax Planck Institute of Experimental MedicineGöttingenGermany
- Electron Microscopy Core UnitMax Planck Institute of Experimental MedicineGöttingenGermany
| | - Leandro Lemgruber
- Glasgow Imaging FacilityInstitute of Infection, Immunity and InflammationCollege of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
| | | | - Klaus‐Armin Nave
- Department of NeurogeneticsMax Planck Institute of Experimental MedicineGöttingenGermany
| | - Anne Boullerne
- Department of AnesthesiologyUniversity of Illinois at ChicagoChicagoIllinoisUSA
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21
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Expression Analysis of Ermin and Listerin E3 Ubiquitin Protein Ligase 1 Genes in the Periphery of Patients with Schizophrenia. J Mol Neurosci 2021; 72:246-254. [PMID: 34676516 DOI: 10.1007/s12031-021-01928-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 10/09/2021] [Indexed: 10/20/2022]
Abstract
Schizophrenia (SCZ) is a severe mental disorder with an unknown etiology. Recent researches indicate that correct myelination and translational regulation play a role in the pathogeny of SCZ. This study evaluated the expression pattern of Ermin (ERMN) and Listerin E3 ubiquitin protein ligase 1 (LTN1) genes, which play a role in myelination and ribosome quality control, respectively. The expression of the ERMN and LTN1 genes in the peripheral blood (PB) of 50 SCZ patients (male/female: 22/28, age (mean ± standard deviation (SD)): 35.9 ± 5.6) and 50 matched healthy controls (male/female: 23/27, age (mean ± SD): 34.7 ± 5.4) were assessed using quantitative polymerase chain reaction. Additionally, we used a bioinformatics approach based on microarray dataset analysis to examine the expression of these two genes in olfactory epithelium (OE) specimens. The expression of ERMN demonstrated no significant differences in PB samples among SCZ patients and healthy controls (adjusted P-value = 0.101). The expression of LTN1 was significantly higher in PB samples obtained from female patients compared with sex-matched controls (posterior beta = 1.734, adjusted P-value < 0.0001). Significant correlations were found between expression of the mentioned genes in PB samples both among SCZ patients and among healthy controls (r = 0.485, P < 0.001 and r = 0.516, P < 0.001, respectively). According to our in silico findings, the ERMN expression levels in OE samples of SCZ were statistically higher than those in controls (log2FC = 1.93, adj.P.Val = 9.66E-15). On the contrary, LTN1 expression levels in OE samples were statistically lower in SCZ cases versus controls (log2FC = - 0.77, adj.P.Val = 2.14E-06). Besides, a significant correlation was found between the expression of the mentioned genes in OE samples (r = - 0.60, P < 0.001). In conclusion, the present study is the first evidence to highlight the expression of the ERMN and LTN1 genes in the periphery of SCZ patients. Our findings may provide light on the SCZ's pathogeny.
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22
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Strawn M, Moraes JGN, Safranski TJ, Behura SK. Sexually Dimorphic Transcriptomic Changes of Developing Fetal Brain Reveal Signaling Pathways and Marker Genes of Brain Cells in Domestic Pigs. Cells 2021; 10:2439. [PMID: 34572090 PMCID: PMC8466205 DOI: 10.3390/cells10092439] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/09/2021] [Accepted: 09/11/2021] [Indexed: 12/13/2022] Open
Abstract
In this study, transcriptomic changes of the developing brain of pig fetuses of both sexes were investigated on gestation days (GD) 45, 60 and 90. Pig fetal brain grows rapidly around GD60. Consequently, gene expression of the fetal brain was distinctly different on GD90 compared to that of GD45 and GD60. In addition, varying numbers of differentially expressed genes (DEGs) were identified in the male brain compared to the female brain during development. The sex of adjacent fetuses also influenced gene expression of the fetal brain. Extensive changes in gene expression at the exon-level were observed during brain development. Pathway enrichment analysis showed that the ionotropic glutamate receptor pathway and p53 pathway were enriched in the female brain, whereas specific receptor-mediated signaling pathways were enriched in the male brain. Marker genes of neurons and astrocytes were significantly differentially expressed between male and female brains during development. Furthermore, comparative analysis of gene expression patterns between fetal brain and placenta suggested that genes related to ion transportation may play a key role in the regulation of the brain-placental axis in pig. Collectively, the study suggests potential application of pig models to better understand influence of fetal sex on brain development.
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Affiliation(s)
- Monica Strawn
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA; (M.S.); (T.J.S.); (J.G.N.M.)
| | - Joao G. N. Moraes
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA; (M.S.); (T.J.S.); (J.G.N.M.)
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK 74075, USA
| | - Timothy J. Safranski
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA; (M.S.); (T.J.S.); (J.G.N.M.)
| | - Susanta K. Behura
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA; (M.S.); (T.J.S.); (J.G.N.M.)
- MU Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65211, USA
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23
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Ahmad I, Wergeland S, Oveland E, Bø L. A higher proportion of ermin-immunopositive oligodendrocytes in areas of remyelination. PLoS One 2021; 16:e0256155. [PMID: 34437581 PMCID: PMC8389439 DOI: 10.1371/journal.pone.0256155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 08/01/2021] [Indexed: 12/03/2022] Open
Abstract
Incomplete remyelination is frequent in multiple sclerosis (MS)-lesions, but there is no established marker for recent remyelination. We investigated the role of the oligodendrocyte/myelin protein ermin in de- and remyelination in the cuprizone (CPZ) mouse model, and in MS. The density of ermin+ oligodendrocytes in the brain was significantly decreased after one week of CPZ exposure (p < 0.02). The relative proportion of ermin+ cells compared to cells positive for the late-stage oligodendrocyte marker Nogo-A increased at the onset of remyelination in the corpus callosum (p < 0.02). The density of ermin-positive cells increased in the corpus callosum during the CPZ-phase of extensive remyelination (p < 0.0001). In MS, the density of ermin+ cells was higher in remyelinated lesion areas compared to non-remyelinated areas both in white- (p < 0.0001) and grey matter (p < 0.0001) and compared to normal-appearing white matter (p < 0.001). Ermin immunopositive cells in MS-lesions were not immunopositive for the early-stage oligodendrocyte markers O4 and O1, but a subpopulation was immunopositive for Nogo-A. The data suggest a relatively higher proportion of ermin immunopositivity in oligodendrocytes compared to Nogo-A indicates recent or ongoing remyelination.
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Affiliation(s)
- Intakhar Ahmad
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Bergen, Norway
| | - Stig Wergeland
- Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Bergen, Norway
| | - Eystein Oveland
- Department of Biomedicine, Proteomics Unit at the University of Bergen (PROBE), University of Bergen, Bergen, Norway
| | - Lars Bø
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Bergen, Norway
- * E-mail:
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24
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Srivastava A, Kumar K, Banerjee J, Tripathi M, Dubey V, Sharma D, Yadav N, Sharma MC, Lalwani S, Doddamani R, Chandra PS, Dixit AB. Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients. Mol Brain 2021; 14:120. [PMID: 34301297 PMCID: PMC8305866 DOI: 10.1186/s13041-021-00832-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 07/14/2021] [Indexed: 11/15/2022] Open
Abstract
Focal cortical dysplasia (FCD) is a malformation of the cerebral cortex with poorly-defined epileptogenic zones (EZs), and poor surgical outcome in FCD is associated with inaccurate localization of the EZ. Hence, identifying novel epileptogenic markers to aid in the localization of EZ in patients with FCD is very much needed. High-throughput gene expression studies of FCD samples have the potential to uncover molecular changes underlying the epileptogenic process and identify novel markers for delineating the EZ. For this purpose, we, for the first time performed RNA sequencing of surgically resected paired tissue samples obtained from electrocorticographically graded high (MAX) and low spiking (MIN) regions of FCD type II patients and autopsy controls. We identified significant changes in the MAX samples of the FCD type II patients when compared to non-epileptic controls, but not in the case of MIN samples. We found significant enrichment for myelination, oligodendrocyte development and differentiation, neuronal and axon ensheathment, phospholipid metabolism, cell adhesion and cytoskeleton, semaphorins, and ion channels in the MAX region. Through the integration of both MAX vs non-epileptic control and MAX vs MIN RNA sequencing (RNA Seq) data, PLP1, PLLP, UGT8, KLK6, SOX10, MOG, MAG, MOBP, ANLN, ERMN, SPP1, CLDN11, TNC, GPR37, SLC12A2, ABCA2, ABCA8, ASPA, P2RX7, CERS2, MAP4K4, TF, CTGF, Semaphorins, Opalin, FGFs, CALB2, and TNC were identified as potential key regulators of multiple pathways related to FCD type II pathology. We have identified novel epileptogenic marker elements that may contribute to epileptogenicity in patients with FCD and could be possible markers for the localization of EZ.
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Affiliation(s)
| | - Krishan Kumar
- Dr B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, India
| | | | | | - Vivek Dubey
- Department of Biophysics, AIIMS, New Delhi, India
| | - Devina Sharma
- Department of Neurosurgery, AIIMS, New Delhi, 110029, India
| | - Nitin Yadav
- Dr B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - M C Sharma
- Department of Pathology, AIIMS, New Delhi, India
| | - Sanjeev Lalwani
- Department of Forensic Medicine and Toxicology, AIIMS, New Delhi, India
| | | | - P Sarat Chandra
- Department of Neurosurgery, AIIMS, New Delhi, 110029, India.
| | - Aparna Banerjee Dixit
- Dr B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, India.
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25
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Shiva S, Gharesouran J, Sabaie H, Asadi MR, Arsang-Jang S, Taheri M, Rezazadeh M. Expression Analysis of Ermin and Listerin E3 Ubiquitin Protein Ligase 1 Genes in Autistic Patients. Front Mol Neurosci 2021; 14:701977. [PMID: 34349621 PMCID: PMC8326841 DOI: 10.3389/fnmol.2021.701977] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/28/2021] [Indexed: 12/27/2022] Open
Abstract
Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that involves social interaction defects, impairment of non-verbal and verbal interactions, and limited interests along with stereotypic activities. Its incidence has been increasing rapidly in recent decades. Despite numerous attempts to understand the pathophysiology of ASD, its exact etiology is still unclear. Recent data shows the role of accurate myelination and translational regulation in ASD's pathogenesis. In this study, we assessed Ermin (ERMN) and Listerin E3 Ubiquitin Protein Ligase 1 (LTN1) genes expression in Iranian ASD patients and age- and gender-matched healthy subjects' peripheral blood using quantitative real-time PCR to recognize any probable dysregulation in the expression of these genes and propose this disorder's mechanisms. Analysis of the expression demonstrated a significant ERMN downregulation in total ASD patients compared to the healthy individuals (posterior beta = -0.794, adjusted P-value = 0.025). LTN1 expression was suggestively higher in ASD patients in comparison with the corresponding control individuals. Considering the gender of study participants, the analysis showed that the mentioned genes' different expression levels were significant only in male subjects. Besides, a significant correlation was found between expression of the mentioned genes (r = -0.49, P < 0.0001). The present study provides further supports for the contribution of ERMN and LTN1 in ASD's pathogenesis.
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Affiliation(s)
- Shadi Shiva
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jalal Gharesouran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hani Sabaie
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Asadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahram Arsang-Jang
- Cancer Gene Therapy Research Center, Zanjan University of Medical Science, Zanjan, Iran
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Rezazadeh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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26
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Ojeda-Pérez B, Campos-Sandoval JA, García-Bonilla M, Cárdenas-García C, Páez-González P, Jiménez AJ. Identification of key molecular biomarkers involved in reactive and neurodegenerative processes present in inherited congenital hydrocephalus. Fluids Barriers CNS 2021; 18:30. [PMID: 34215285 PMCID: PMC8254311 DOI: 10.1186/s12987-021-00263-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 06/19/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Periventricular extracellular oedema, myelin damage, inflammation, and glial reactions are common neuropathological events that occur in the brain in congenital hydrocephalus. The periventricular white matter is the most affected region. The present study aimed to identify altered molecular and cellular biomarkers in the neocortex that can function as potential therapeutic targets to both treat and evaluate recovery from these neurodegenerative conditions. The hyh mouse model of hereditary hydrocephalus was used for this purpose. METHODS The hyh mouse model of hereditary hydrocephalus (hydrocephalus with hop gait) and control littermates without hydrocephalus were used in the present work. In tissue sections, the ionic content was investigated using energy dispersive X-ray spectroscopy scanning electron microscopy (EDS-SEM). For the lipid analysis, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was performed in frozen sections. The expression of proteins in the cerebral white matter was analysed by mass spectrometry. The oligodendrocyte progenitor cells (OPCs) were studied with immunofluorescence in cerebral sections and whole-mount preparations of the ventricle walls. RESULTS High sodium and chloride concentrations were found indicating oedema conditions in both the periventricular white matter and extending towards the grey matter. Lipid analysis revealed lower levels of two phosphatidylinositol molecular species in the grey matter, indicating that neural functions were altered in the hydrocephalic mice. In addition, the expression of proteins in the cerebral white matter revealed evident deregulation of the processes of oligodendrocyte differentiation and myelination. Because of the changes in oligodendrocyte differentiation in the white matter, OPCs were also studied. In hydrocephalic mice, OPCs were found to be reactive, overexpressing the NG2 antigen but not giving rise to an increase in mature oligodendrocytes. The higher levels of the NG2 antigen, diacylglycerophosphoserine and possibly transthyretin in the cerebrum of hydrocephalic hyh mice could indicate cell reactions that may have been triggered by inflammation, neurocytotoxic conditions, and ischaemia. CONCLUSION Our results identify possible biomarkers of hydrocephalus in the cerebral grey and white matter. In the white matter, OPCs could be reacting to acquire a neuroprotective role or as a delay in the oligodendrocyte maturation.
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Affiliation(s)
- Betsaida Ojeda-Pérez
- Department of Cell Biology, Genetics, and Physiology, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Malaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Malaga, Spain
| | - José A Campos-Sandoval
- Servicios Centrales de Apoyo a la Investigación (SCAI), Universidad de Malaga, Malaga, Spain
| | - María García-Bonilla
- Department of Cell Biology, Genetics, and Physiology, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Malaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Malaga, Spain
| | | | - Patricia Páez-González
- Department of Cell Biology, Genetics, and Physiology, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Malaga, Spain.
- Instituto de Investigación Biomédica de Málaga (IBIMA), Malaga, Spain.
| | - Antonio J Jiménez
- Department of Cell Biology, Genetics, and Physiology, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Malaga, Spain.
- Instituto de Investigación Biomédica de Málaga (IBIMA), Malaga, Spain.
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27
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Leitner DF, Mills JD, Pires G, Faustin A, Drummond E, Kanshin E, Nayak S, Askenazi M, Verducci C, Chen BJ, Janitz M, Anink JJ, Baayen JC, Idema S, van Vliet EA, Devore S, Friedman D, Diehl B, Scott C, Thijs R, Wisniewski T, Ueberheide B, Thom M, Aronica E, Devinsky O. Proteomics and Transcriptomics of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Patients. Neurology 2021; 96:e2639-e2652. [PMID: 33910938 PMCID: PMC8205452 DOI: 10.1212/wnl.0000000000011999] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 02/26/2021] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE To identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to control patients with epilepsy. METHODS For proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected postmortem brain tissue of 12 patients with SUDEP and 14 with non-SUDEP epilepsy. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from patients with mesial temporal lobe epilepsy: 6 low-risk and 8 high-risk SUDEP as determined by a short (<50 seconds) or prolonged (≥50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes. RESULTS In autopsy hippocampus and cortex, we observed no proteomic differences between patients with SUDEP and those with non-SUDEP epilepsy, contrasting with our previously reported robust differences between epilepsy and controls without epilepsy. Transcriptomics in hippocampus and cortex from patients with surgical epilepsy segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 long noncoding RNAs, 3 pending) in hippocampus. CONCLUSION The SUDEP proteome and high-risk SUDEP transcriptome were similar to those in other patients with epilepsy in hippocampus and cortex, consistent with diverse epilepsy syndromes and comorbid conditions associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions, may identify molecular mechanisms of SUDEP.
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Affiliation(s)
- Dominique F Leitner
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - James D Mills
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Geoffrey Pires
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Arline Faustin
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Eleanor Drummond
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Evgeny Kanshin
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Shruti Nayak
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Manor Askenazi
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Chloe Verducci
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Bei Jun Chen
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Michael Janitz
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Jasper J Anink
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Johannes C Baayen
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Sander Idema
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Erwin A van Vliet
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Sasha Devore
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Daniel Friedman
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Beate Diehl
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Catherine Scott
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Roland Thijs
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Thomas Wisniewski
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Beatrix Ueberheide
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Maria Thom
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Eleonora Aronica
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
| | - Orrin Devinsky
- From the Comprehensive Epilepsy Center (D.F.L., C.V., S.D., D.F., O.D.), Proteomics Laboratory (E.K., S.N., B.U.), Division of Advanced Research Technologies, and Department of Biochemistry and Molecular Pharmacology (B.U.), NYU School of Medicine; Department of Neurology (D.F.L., G.P., A.F., E.D., S.D., D.F., T.W., B.U., O.D.), Center for Cognitive Neurology (G.P., A.F., E.D., T.W.), Department of Pathology (T.W.), and Department of Psychiatry (T.W.), NYU Langone Health and School of Medicine, New York; Department of (Neuro)Pathology (J.D.M., J.J.A., E.A.v.V., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, the Netherlands; Alzheimer's and Prion Diseases Team (G.P.), Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France; Brain & Mind Centre and School of Medical Sciences (E.D.), Faculty of Medicine and Health, University of Sydney, Australia; Biomedical Hosting LLC (M.A.), Arlington, MA; School of Biotechnology and Biomolecular Sciences (B.J.C., M.J.), University of New South Wales, Sydney, Australia; Amsterdam UMC (J.C.B., S.I.), Vrije Universiteit Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, De Boelelaan 1117; Swammerdam Institute for Life Sciences (E.A.v.V.), Center for Neuroscience, University of Amsterdam, the Netherlands; Department of Clinical and Experimental Epilepsy (B.D., C.S., M.T.), University College London Institute of Neurology, UK; and Stichting Epilepsie Instellingen Nederland (R.T., E.A.), Heemstede, the Netherlands
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Oveland E, Ahmad I, Lereim RR, Kroksveen AC, Barsnes H, Guldbrandsen A, Myhr KM, Bø L, Berven FS, Wergeland S. Cuprizone and EAE mouse frontal cortex proteomics revealed proteins altered in multiple sclerosis. Sci Rep 2021; 11:7174. [PMID: 33785790 PMCID: PMC8010076 DOI: 10.1038/s41598-021-86191-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 02/19/2021] [Indexed: 02/06/2023] Open
Abstract
Two pathophysiological different experimental models for multiple sclerosis were analyzed in parallel using quantitative proteomics in attempts to discover protein alterations applicable as diagnostic-, prognostic-, or treatment targets in human disease. The cuprizone model reflects de- and remyelination in multiple sclerosis, and the experimental autoimmune encephalomyelitis (EAE, MOG1-125) immune-mediated events. The frontal cortex, peripheral to severely inflicted areas in the CNS, was dissected and analyzed. The frontal cortex had previously not been characterized by proteomics at different disease stages, and novel protein alterations involved in protecting healthy tissue and assisting repair of inflicted areas might be discovered. Using TMT-labelling and mass spectrometry, 1871 of the proteins quantified overlapped between the two experimental models, and the fold change compared to controls was verified using label-free proteomics. Few similarities in frontal cortex between the two disease models were observed when regulated proteins and signaling pathways were compared. Legumain and C1Q complement proteins were among the most upregulated proteins in cuprizone and hemopexin in the EAE model. Immunohistochemistry showed that legumain expression in post-mortem multiple sclerosis brain tissue (n = 19) was significantly higher in the center and at the edge of white matter active and chronic active lesions. Legumain was associated with increased lesion activity and might be valuable as a drug target using specific inhibitors as already suggested for Parkinson's and Alzheimer's disease. Cerebrospinal fluid levels of legumain, C1q and hemopexin were not significantly different between multiple sclerosis patients, other neurological diseases, or healthy controls.
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Affiliation(s)
- Eystein Oveland
- Proteomics Unit, Department of Biomedicine, University of Bergen (PROBE), Bergen, Norway
| | - Intakhar Ahmad
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Jonas Lies vei 65, 5021, Bergen, Norway
| | - Ragnhild Reehorst Lereim
- Proteomics Unit, Department of Biomedicine, University of Bergen (PROBE), Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Ann Cathrine Kroksveen
- Proteomics Unit, Department of Biomedicine, University of Bergen (PROBE), Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Harald Barsnes
- Proteomics Unit, Department of Biomedicine, University of Bergen (PROBE), Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Astrid Guldbrandsen
- Proteomics Unit, Department of Biomedicine, University of Bergen (PROBE), Bergen, Norway
- Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Jonas Lies vei 65, 5021, Bergen, Norway
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
| | - Kjell-Morten Myhr
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Lars Bø
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Jonas Lies vei 65, 5021, Bergen, Norway
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Frode S Berven
- Proteomics Unit, Department of Biomedicine, University of Bergen (PROBE), Bergen, Norway
- Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Jonas Lies vei 65, 5021, Bergen, Norway
| | - Stig Wergeland
- Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Jonas Lies vei 65, 5021, Bergen, Norway.
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.
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A Human Retinal Pigment Epithelium-Based Screening Platform Reveals Inducers of Photoreceptor Outer Segments Phagocytosis. Stem Cell Reports 2020; 15:1347-1361. [PMID: 33242397 PMCID: PMC7724476 DOI: 10.1016/j.stemcr.2020.10.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 11/20/2022] Open
Abstract
Phagocytosis is a key function in various cells throughout the body. A deficiency in photoreceptor outer segment (POS) phagocytosis by the retinal pigment epithelium (RPE) causes vision loss in inherited retinal diseases and possibly age-related macular degeneration. To date, there are no effective therapies available aiming at recovering the lost phagocytosis function. Here, we developed a high-throughput screening assay based on RPE derived from human embryonic stem cells (hRPE) to reveal enhancers of POS phagocytosis. One of the hits, ramoplanin (RM), reproducibly enhanced POS phagocytosis and ensheathment in hRPE, and enhanced the expression of proteins known to regulate membrane dynamics and ensheathment in other cell systems. Additionally, RM rescued POS internalization defect in Mer receptor tyrosine kinase (MERTK) mutant hRPE, derived from retinitis pigmentosa patient induced pluripotent stem cells. Our platform, including a primary phenotypic screening phagocytosis assay together with orthogonal assays, establishes a basis for RPE-based therapy discovery aiming at a broad patient spectrum.
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Wang S, Wang T, Liu T, Xie RG, Zhao XH, Wang L, Yang Q, Jia LT, Han J. Ermin is a p116 RIP -interacting protein promoting oligodendroglial differentiation and myelin maintenance. Glia 2020; 68:2264-2276. [PMID: 32530539 DOI: 10.1002/glia.23838] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 04/17/2020] [Accepted: 04/21/2020] [Indexed: 12/21/2022]
Abstract
Myelin sheaths, which insulate the axons and ensure saltatory conduction of the nerve impulse, are generated and maintained via largely uncharacterized mechanisms. Ermin is an oligodendrocyte-specific protein associated with the cytoskeleton, but how it regulates cytoskeletal remodeling during oligodendrocyte differentiation and its role in myelin maintenance are not clear. To address this, we generated mice constitutively deficient for Ermn, the Ermin-coding gene. We found that aged Ermn-knockout mice exhibit an aberrant myelin architecture, with splitting of myelin layers, peeling of the myelin sheath from axons, and breakdown of myelinated fibers. As a result, these mice had remarkably impaired motor coordination. Ermn knockout also accelerated cuprizone-induced demyelination and exacerbated the associated movement disorders. Ermin was found to contribute to oligodendrocyte morphogenesis by associating with the myosin phosphatase Rho interacting protein (Mprip/p116RIP ) and inactivating RhoA, a GTPase that controls cytoskeletal rearrangement in differentiating cells. These findings provide novel insights into the mechanisms regulating oligodendroglial differentiation, the maintenance of the myelin sheaths, and remyelination.
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Affiliation(s)
- Shan Wang
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Tao Wang
- Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Tao Liu
- Key Laboratory of Modern Teaching Technology, Shaanxi Normal University, Xi'an, China
| | - Rou-Gang Xie
- Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China
| | - Xiang-Hui Zhao
- Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China
| | - Lei Wang
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Qian Yang
- Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Lin-Tao Jia
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Jing Han
- Key Laboratory of Modern Teaching Technology, Shaanxi Normal University, Xi'an, China
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Abstract
The central nervous system is simply divided into two distinct anatomical regions based on the color of tissues, i.e. the gray and white matter. The gray matter is composed of neuronal cell bodies, glial cells, dendrites, immune cells, and the vascular system, while the white matter is composed of concentrated myelinated axonal fibers extending from neuronal soma and glial cells, such as oligodendrocyte precursor cells (OPCs), oligodendrocytes, astrocytes, and microglia. As neuronal cell bodies are located in the gray matter, great attention has been focused mainly on the gray matter regarding the understanding of the functions of the brain throughout the neurophysiological areas, leading to a scenario in which the function of the white matter is relatively underestimated or has not received much attention. However, increasing evidence shows that the white matter plays highly significant and pivotal functions in the brain based on the fact that its abnormalities are associated with numerous neurological diseases. In this review, we will broadly discuss the pathways and functions of myelination, which is one of the main processes that modulate the functions of the white matter, as well as the manner in which its abnormalities are related to neurological disorders.
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Carroll JA, Race B, Williams K, Striebel J, Chesebro B. RNA-seq and network analysis reveal unique glial gene expression signatures during prion infection. Mol Brain 2020; 13:71. [PMID: 32381108 PMCID: PMC7206698 DOI: 10.1186/s13041-020-00610-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 04/24/2020] [Indexed: 02/01/2023] Open
Abstract
Background Prion diseases and prion-like disorders, including Alzheimer’s disease and Parkinson’s disease, are characterized by gliosis and accumulation of misfolded aggregated host proteins. Ablating microglia in prion-infected brain by treatment with the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, PLX5622, increased accumulation of misfolded prion protein and decreased survival time. Methods To better understand the role of glia during neurodegeneration, we used RNA-seq technology, network analysis, and hierarchical cluster analysis to compare gene expression in brains of prion-infected versus mock-inoculated mice. Comparisons were also made between PLX5622-treated prion-infected mice and untreated prion-infected mice to assess mechanisms involved in disease acceleration in the absence of microglia. Results RNA-seq and network analysis suggested that microglia responded to prion infection through activation of integrin CD11c/18 and did not adopt the expression signature associated with other neurodegenerative disease models. Instead, microglia acquired an alternative molecular signature late in the disease process. Furthermore, astrocytes expressed a signature pattern of genes which appeared to be specific for prion diseases. Comparisons were also made with prion-infected mice treated with PLX5622 to assess the impact of microglia ablation on astrocyte gene expression during prion infection. In the presence of microglia, a unique mix of transcripts associated with A1- and A2-reactive astrocytes was increased in brains of prion-infected mice. After ablation of microglia, this reactive astrocyte expression pattern was enhanced. Thus, after prion infection, microglia appeared to decrease the overall A1/A2-astrocyte responses which might contribute to increased survival after infection. Conclusions RNA-seq analysis indicated dysregulation of over 300 biological processes within the CNS during prion disease. Distinctive microglia- and astrocyte-associated expression signatures were identified during prion infection. Furthermore, astrogliosis and the unique astrocyte-associated expression signature were independent of microglial influences. Astrogliosis and the unique astrocyte-associated gene expression pattern were increased when microglia were ablated. Our findings emphasize the potential existence of alternative pathways for activating the A1/A2 paradigm in astrocytes during neurodegenerative disease.
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Affiliation(s)
- James A Carroll
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South Fourth Street, Hamilton, MT, 59840, USA.
| | - Brent Race
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South Fourth Street, Hamilton, MT, 59840, USA
| | - Katie Williams
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South Fourth Street, Hamilton, MT, 59840, USA
| | - James Striebel
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South Fourth Street, Hamilton, MT, 59840, USA
| | - Bruce Chesebro
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South Fourth Street, Hamilton, MT, 59840, USA
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Ranard KM, Kuchan MJ, Bruno RS, Juraska JM, Erdman JW. Synthetic α-Tocopherol, Compared with Natural α-Tocopherol, Downregulates Myelin Genes in Cerebella of Adolescent Ttpa-null Mice. J Nutr 2020; 150:1031-1040. [PMID: 31883016 DOI: 10.1093/jn/nxz330] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/01/2019] [Accepted: 12/09/2019] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Vitamin E (α-tocopherol; α-T) deficiency causes spinocerebellar ataxia. α-T supplementation improves neurological symptoms, but little is known about the differential bioactivities of natural versus synthetic α-T during early life. OBJECTIVE We assessed the effects of dietary α-T dose and source on tissue α-T accumulation and gene expression in adolescent α-tocopherol transfer protein-null (Ttpa-/-) mice. METHODS Three-week-old male Ttpa-/- mice (n = 7/group) were fed 1 of 4 AIN-93G-based diets for 4 wk: vitamin E deficient (VED; below α-T limit of detection); natural α-T, 600 mg/kg diet (NAT); synthetic α-T, 816 mg/kg diet (SYN); or high synthetic α-T, 1200 mg/kg diet (HSYN). Male Ttpa+/+ littermates fed AIN-93G [75 mg synthetic α-T (CON)] served as controls (n = 7). At 7 wk of age, tissue α-T concentrations and stereoisomer profiles were measured for all groups. RNA-sequencing was performed on cerebella of Ttpa-/- groups. RESULTS Ttpa-/- mice fed VED had undetectable brain α-T concentrations. Cerebral cortex α-T concentrations were greater in Ttpa-/- mice fed NAT (9.1 ± 0.7 nmol/g), SYN (10.8 ± 1.0 nmol/g), and HSYN (13.9 ± 1.6 nmol/g) compared with the VED group but were significantly lower than in Ttpa+/+ mice fed CON (24.6 ± 1.2 nmol/g) (P < 0.001). RRR-α-T was the predominant stereoisomer in brains of Ttpa+/+ mice (∼40%) and Ttpa-/- mice fed NAT (∼94%). α-T stereoisomer composition was similar in brains of Ttpa-/- mice fed SYN and HSYN (2R: ∼53%; 2S: ∼47%). Very few of the 16,774 genes measured were differentially expressed. However, compared with the NAT diet, HSYN significantly downregulated 20 myelin genes, including 2 transcription factors: SRY-box transcription factor 10 (Sox10) and myelin regulatory factor (Myrf), and several downstream target genes (false discovery rate <0.05). CONCLUSIONS High-dose synthetic α-T compared with natural α-T alters myelin gene expression in the adolescent mouse cerebellum, which could lead to morphological and functional abnormalities later in life.
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Affiliation(s)
- Katherine M Ranard
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | | | - Richard S Bruno
- Human Nutrition Program, The Ohio State University, Columbus, OH, USA
| | - Janice M Juraska
- Department of Psychology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - John W Erdman
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, USA
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Sustentacular Cell Enwrapment of Olfactory Receptor Neuronal Dendrites: An Update. Genes (Basel) 2020; 11:genes11050493. [PMID: 32365880 PMCID: PMC7291085 DOI: 10.3390/genes11050493] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/23/2020] [Accepted: 04/27/2020] [Indexed: 12/12/2022] Open
Abstract
The pseudostratified olfactory epithelium (OE) may histologically appear relatively simple, but the cytological relations among its cell types, especially those between olfactory receptor neurons (ORNs) and olfactory sustentacular cells (OSCs), prove more complex and variable than previously believed. Adding to the complexity is the short lifespan, persistent neurogenesis, and continuous rewiring of the ORNs. Contrary to the common belief that ORN dendrites are mostly positioned between OSCs, recent findings indicate a sustentacular cell enwrapped configuration for a majority of mature ORN dendrites at the superficial layer of the OE. After vertically sprouting out from the borderlines between OSCs, most of the immature ORN dendrites undergo a process of sideways migration and terminal maturation to become completely invaginated into and enwrapped by OSCs. Trailing the course of the dendritic sideways migration is the mesodendrite (mesentery of the enwrapped dendrite) made of closely apposed, cell junction connected plasma membrane layers of neighboring folds of the host sustentacular cell. Only a minority of the mature ORN dendrites at the OE apical surface are found at the borderlines between OSCs (unwrapped). Below I give a brief update on the cytoarchitectonic relations between the ORNs and OSCs of the OE. Emphasis is placed on the enwrapment of ORN dendrites by OSCs, on the sideways migration of immature ORN dendrites after emerging from the OE surface, and on the terminal maturation of the ORNs. Functional implications of ORN dendrite enwrapment and a comparison with myelination or Remak’s bundling of axons or axodendrites in the central and peripheral nervous system are also discussed.
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Szilagyi GT, Nawrocki AM, Eros K, Schmidt J, Fekete K, Elkjaer ML, Hyrlov KH, Larsen MR, Illes Z, Gallyas F. Proteomic changes during experimental de- and remyelination in the corpus callosum. PLoS One 2020; 15:e0230249. [PMID: 32272486 PMCID: PMC7145428 DOI: 10.1371/journal.pone.0230249] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 02/25/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND In the cuprizone model of multiple sclerosis, de- and remyelination can be studied without major interference from the adaptive immune responses. Since previous proteomic studies did not focus on the corpus callosum, where cuprizone causes the most pronounced demyelination, we performed a bottom up proteomic analysis on this brain region. METHODS Eight week-old mice treated with 0.2% cuprizone, for 4 weeks and controls (C) were sacrificed after termination of the treatment (4wD), and 2 (2dR) or 14 (2wR) days later. Homogenates of dissected corpus callosum were analysed by quantitative proteomics. For data processing, clustering, gene ontology analysis, and regulatory network prediction, we used Perseus, PANTHER and Ingenuity Pathway Analysis softwares, respectively. RESULTS We identified 4886 unmodified, single- or multi phosphorylated and/or gycosylated (PTM) proteins. Out of them, 191 proteins were differentially regulated in at least one experimental group. We found 57 proteins specific for demyelination, 27 for early- and 57 for late remyelinationwhile 36 proteins were affected in two, and 23 proteins in all three groups. Phosphorylation represented 92% of the post translational modifications among differentially regulated modified (PTM) proteins with decreased level, while it was only 30% of the PTM proteins with increased level. Gene ontology analysis could not classify the demyelination specific proteins into any biological process category, while allocated the remyelination specific ones to nervous system development and myelination as the most specific subcategory. We also identified a protein network in experimental remyelination, and the gene orthologues of the network were differentially expressed in remyelinating multiple sclerosis brain lesions consistent with an early remyelination pattern. CONCLUSION Proteomic analysis seems more informative for remyelination than demyelination in the cuprizone model.
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Affiliation(s)
- Gabor T. Szilagyi
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, Pécs, Hungary
| | - Arkadiusz M. Nawrocki
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Krisztian Eros
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, Pécs, Hungary
- Szentagothai Research Centre, University of Pécs, Pécs, Hungary
- Nuclear-Mitochondrial Interactions Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | - Janos Schmidt
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, Pécs, Hungary
| | - Katalin Fekete
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, Pécs, Hungary
| | - Maria L. Elkjaer
- Department of Neurology, Odense University Hospital, Odense, Denmark
| | - Kirsten H. Hyrlov
- Department of Neurology, Odense University Hospital, Odense, Denmark
| | - Martin R. Larsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Zsolt Illes
- Department of Neurology, Odense University Hospital, Odense, Denmark
- Institute of Clinical Research, BRIDGE University of Southern Denmark, Odense, Denmark
- Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Ferenc Gallyas
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, Pécs, Hungary
- Szentagothai Research Centre, University of Pécs, Pécs, Hungary
- Nuclear-Mitochondrial Interactions Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- * E-mail:
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Raasakka A, Kursula P. Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease. Cells 2020; 9:cells9020470. [PMID: 32085570 PMCID: PMC7072810 DOI: 10.3390/cells9020470] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/16/2020] [Accepted: 02/16/2020] [Indexed: 02/07/2023] Open
Abstract
Myelin ensheathes selected axonal segments within the nervous system, resulting primarily in nerve impulse acceleration, as well as mechanical and trophic support for neurons. In the central and peripheral nervous systems, various proteins that contribute to the formation and stability of myelin are present, which also harbor pathophysiological roles in myelin disease. Many myelin proteins have common attributes, including small size, hydrophobic segments, multifunctionality, longevity, and regions of intrinsic disorder. With recent advances in protein biophysical characterization and bioinformatics, it has become evident that intrinsically disordered proteins (IDPs) are abundant in myelin, and their flexible nature enables multifunctionality. Here, we review known myelin IDPs, their conservation, molecular characteristics and functions, and their disease relevance, along with open questions and speculations. We place emphasis on classifying the molecular details of IDPs in myelin, and we correlate these with their various functions, including susceptibility to post-translational modifications, function in protein–protein and protein–membrane interactions, as well as their role as extended entropic chains. We discuss how myelin pathology can relate to IDPs and which molecular factors are potentially involved.
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Affiliation(s)
- Arne Raasakka
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, NO-5009 Bergen, Norway;
| | - Petri Kursula
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, NO-5009 Bergen, Norway;
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Aapistie 7A, FI-90220 Oulu, Finland
- Correspondence:
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Radulescu CI, Garcia-Miralles M, Sidik H, Bardile CF, Yusof NABM, Lee HU, Ho EXP, Chu CW, Layton E, Low D, De Sessions PF, Pettersson S, Ginhoux F, Pouladi MA. Reprint of: Manipulation of microbiota reveals altered callosal myelination and white matter plasticity in a model of Huntington disease. Neurobiol Dis 2020; 135:104744. [PMID: 31931139 DOI: 10.1016/j.nbd.2020.104744] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 02/02/2019] [Accepted: 02/20/2019] [Indexed: 12/19/2022] Open
Abstract
Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and oligodendroglial population dynamics in the mixed-sex BACHD mouse model of HD. Ultrastructural analysis of myelin in the corpus callosum revealed alterations of myelin thickness in BACHD GF compared to specific-pathogen free (SPF) mice, whereas no differences were observed between wild-type (WT) groups. In contrast, myelin compaction was altered in all groups when compared to WT SPF animals. Levels of myelin-related proteins were generally reduced, and the number of mature oligodendrocytes was decreased in the prefrontal cortex under GF compared to SPF conditions, regardless of genotype. Minor differences in commensal bacteria at the family and genera levels were found in the gut microbiota of BACHD and WT animals housed in standard living conditions. Our findings indicate complex effects of a germ-free status on myelin-related characteristics, and highlight the adaptive properties of myelination as a result of environmental manipulation.
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Affiliation(s)
- Carola I Radulescu
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 138648, Singapore; Department of Psychology, The University of Sheffield, S1 2LT, UK
| | - Marta Garcia-Miralles
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 138648, Singapore
| | - Harwin Sidik
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 138648, Singapore
| | - Costanza Ferrari Bardile
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 138648, Singapore
| | - Nur Amirah Binte Mohammad Yusof
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 138648, Singapore
| | - Hae Ung Lee
- Lee Kong Chian School of Medicine, Nanyang Technological University, 637551, Singapore
| | - Eliza Xin Pei Ho
- GIS Efficient Rapid Microbial Sequencing, Genome Institute of Singapore, A*STAR, 138672, Singapore
| | - Collins Wenhan Chu
- GIS Efficient Rapid Microbial Sequencing, Genome Institute of Singapore, A*STAR, 138672, Singapore
| | - Emma Layton
- GIS Efficient Rapid Microbial Sequencing, Genome Institute of Singapore, A*STAR, 138672, Singapore
| | - Donovan Low
- Singapore Immunology Network, A*STAR, 138648, Singapore
| | - Paola Florez De Sessions
- GIS Efficient Rapid Microbial Sequencing, Genome Institute of Singapore, A*STAR, 138672, Singapore
| | - Sven Pettersson
- Lee Kong Chian School of Medicine, Nanyang Technological University, 637551, Singapore; Singapore Centre for Environmental Life Sciences Engineering, 60 Nanyang Drive, 637551, Singapore
| | | | - Mahmoud A Pouladi
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 138648, Singapore; Department of Medicine, National University of Singapore, 117597, Singapore; Department of Physiology, National University of Singapore, 117597, Singapore.
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Thomason EJ, Escalante M, Osterhout DJ, Fuss B. The oligodendrocyte growth cone and its actin cytoskeleton: A fundamental element for progenitor cell migration and CNS myelination. Glia 2019; 68:1329-1346. [PMID: 31696982 DOI: 10.1002/glia.23735] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 09/26/2019] [Accepted: 10/01/2019] [Indexed: 01/06/2023]
Abstract
Cells of the oligodendrocyte (OLG) lineage engage in highly motile behaviors that are crucial for effective central nervous system (CNS) myelination. These behaviors include the guided migration of OLG progenitor cells (OPCs), the surveying of local environments by cellular processes extending from differentiating and pre-myelinating OLGs, and during the process of active myelin wrapping, the forward movement of the leading edge of the myelin sheath's inner tongue along the axon. Almost all of these motile behaviors are driven by actin cytoskeletal dynamics initiated within a lamellipodial structure that is located at the tip of cellular OLG/OPC processes and is structurally as well as functionally similar to the neuronal growth cone. Accordingly, coordinated stoichiometries of actin filament (F-actin) assembly and disassembly at these OLG/OPC growth cones have been implicated in directing process outgrowth and guidance, and the initiation of myelination. Nonetheless, the functional importance of the OLG/OPC growth cone still remains to be fully understood, and, as a unique aspect of actin cytoskeletal dynamics, F-actin depolymerization and disassembly start to predominate at the transition from myelination initiation to myelin wrapping. This review provides an overview of the current knowledge about OLG/OPC growth cones, and it proposes a model in which actin cytoskeletal dynamics in OLG/OPC growth cones are a main driver for morphological transformations and motile behaviors. Remarkably, these activities, at least at the later stages of OLG maturation, may be regulated independently from the transcriptional gene expression changes typically associated with CNS myelination.
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Affiliation(s)
- Elizabeth J Thomason
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Miguel Escalante
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia.,Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Donna J Osterhout
- Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, New York
| | - Babette Fuss
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
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Salek Esfahani B, Gharesouran J, Ghafouri-Fard S, Talebian S, Arsang-Jang S, Omrani MD, Taheri M, Rezazadeh M. Down-regulation of ERMN expression in relapsing remitting multiple sclerosis. Metab Brain Dis 2019; 34:1261-1266. [PMID: 31123898 DOI: 10.1007/s11011-019-00429-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/10/2019] [Indexed: 12/13/2022]
Abstract
Multiple Sclerosis (MS) is a chronic inflammatory disease causing demyelination and neurodegeneration in the central nervous system (CNS). Although the exact etiology of MS is still unclear, both genetic and environmental elements are regarded as causative factors. Environmental factors can induce a cascade of events in immune system leading to neuronal death and nerve demyelination. This paper aims to compare the peripheral transcript levels of Ermin (ERMN) (a gene with putative role in cytoskeletal rearrangements during myelinogenesis) and Listerin E3 Ubiquitin Protein Ligase 1 (LTN1) (a gene with functions in regulating innate immune system) between relapsing-remitting MS (RR-MS) patients and healthy controls. The results showed a significant decrease in ERMN expression (p = 0.022); whereas, no significant difference was detected in LTN1 expression between two groups (p = 0.935). The reduction in ERMN expression in leukocytes could be the cause of demyelinating process in RR-MS patients. Current findings might also have practical importance in prognosis and targeted therapies.
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Affiliation(s)
- Behnaz Salek Esfahani
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jalal Gharesouran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahrzad Talebian
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahram Arsang-Jang
- Clinical Research Development Center (CRDU), Qom University of Medical Sciences, Qom, Iran
| | - Mir Davood Omrani
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maryam Rezazadeh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Zyla K, Larabee CM, Georgescu C, Berkley C, Reyna T, Plafker SM. Dimethyl fumarate mitigates optic neuritis. Mol Vis 2019; 25:446-461. [PMID: 31523122 PMCID: PMC6707756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 08/20/2019] [Indexed: 11/07/2022] Open
Abstract
Purpose Dimethyl fumarate (DMF) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing-remitting multiple sclerosis (RRMS), a demyelinating autoimmune disease characterized by acute episodes of motor, sensory, and cognitive symptoms. Optic neuritis is an episodic sequela experienced by some patients with RRMS that typically presents as acute, monocular vision loss. Episodes of optic neuritis damage and kill retinal ganglion cells (RGCs), and can culminate in permanent vision loss. The purpose of these studies was to evaluate the capacity of DMF to mitigate optic neuritis. The work presented combines studies of a mouse model of MS and a retrospective chart analysis of files of patients with RRMS treated at the MS Center of Excellence within the Oklahoma Medical Research Foundation. Methods Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model that recapitulates cardinal features of somatic and visual MS pathologies. EAE was induced in female C57BL/6J mice by inoculation with myelin oligodendrocyte glycoprotein peptide (residues 35-55; MOG35-55). DMF or vehicle was administered twice a day by oral gavage. Visual acuity was measured longitudinally with optokinetic tracking. Post-mortem analyses included quantification of RGCs in retinal flatmounts and quantitative PCR (qPCR) of Nrf2 target genes and regulators of myelin. Retrospective chart analyses were performed using data obtained from deidentified files of patients with RRMS. Results In the EAE mouse studies, DMF decreased optic neuritis severity, preserved vision and RGCs, and concomitantly reduced motor deficits when administered by two different treatment regimens (prevention or interventional). DMF was more efficacious when administered as an interventional therapy, and the beneficial effects occurred independently of the induction of Nrf2 target genes. A complementary retrospective chart analysis demonstrated that DMF increased the time to a recurrence of optic neuritis, and protected against subsequent bouts of optic neuritis. Conclusions This work underscores the potential of DMF to mitigate the severity and recurrence of optic neuritis episodes in patients with RRMS.
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Affiliation(s)
- Katarzyna Zyla
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK,Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Chelsea M. Larabee
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK,Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Constantin Georgescu
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
| | - Chelsea Berkley
- The Oklahoma Medical Research Foundation Multiple Sclerosis Center of Excellence, Oklahoma City, OK
| | - Tania Reyna
- The Oklahoma Medical Research Foundation Multiple Sclerosis Center of Excellence, Oklahoma City, OK
| | - Scott M. Plafker
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK,Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK,Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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Shi W, Hegeman MA, Doncheva A, van der Stelt I, Bekkenkamp‐Grovenstein M, van Schothorst EM, Brenner C, de Boer VCJ, Keijer J. Transcriptional Response of White Adipose Tissue to Withdrawal of Vitamin B3. Mol Nutr Food Res 2019; 63:e1801100. [PMID: 30990964 PMCID: PMC6618275 DOI: 10.1002/mnfr.201801100] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 03/11/2019] [Indexed: 01/24/2023]
Abstract
SCOPE Distinct markers for mild vitamin B3 deficiency are lacking. To identify these, the molecular responses of white adipose tissue (WAT) to vitamin B3 withdrawal are examined. METHODS AND RESULTS A dietary intervention is performed in male C57BL/6JRccHsd mice, in which a diet without nicotinamide riboside (NR) is compared to a diet with NR at the recommended vitamin B3 level. Both diets contain low but adequate level of tryptophan. Metabolic flexibility and systemic glucose tolerance are analyzed and global transcriptomics, qRT-PCR, and histology of epididymal WAT (eWAT) are performed. A decreased insulin sensitivity and a shift from carbohydrate to fatty acid oxidation in response to vitamin B3 withdrawal are observed. This is consistent with molecular changes in eWAT, including an activated MEK/ERK signaling, a lowering of glucose utilization markers, and an increase in makers of fatty acid catabolism, possibly related to the consistent lower expression of mitochondrial electron transport complexes. The synthesis pathway of tetrahydropteridine (BH4), an essential cofactor for neurotransmitter synthesis, is transcriptionally activated. Genes marking these processes are technically validated. CONCLUSION The downregulation of Anp32a, Tnk2 and the upregulation of Mapk1, Map2k1, Qdpr, Mthfs, and Mthfsl are proposed as a WAT transcriptional signature marker for mild vitamin B3 deficiency.
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Affiliation(s)
- Wenbiao Shi
- Human and Animal PhysiologyWageningen UniversityPO Box 3386700AHWageningenThe Netherlands
| | - Maria A. Hegeman
- Human and Animal PhysiologyWageningen UniversityPO Box 3386700AHWageningenThe Netherlands
- Educational Consultancy & Professional DevelopmentFaculty of Social and Behavioural Sciences, Utrecht University3584CSUtrechtThe Netherlands
| | - Atanaska Doncheva
- Human and Animal PhysiologyWageningen UniversityPO Box 3386700AHWageningenThe Netherlands
| | - Inge van der Stelt
- Human and Animal PhysiologyWageningen UniversityPO Box 3386700AHWageningenThe Netherlands
| | | | | | - Charles Brenner
- Department of BiochemistryCarver College of Medicine, University of IowaIowa CityIA52242USA
| | - Vincent C. J. de Boer
- Human and Animal PhysiologyWageningen UniversityPO Box 3386700AHWageningenThe Netherlands
| | - Jaap Keijer
- Human and Animal PhysiologyWageningen UniversityPO Box 3386700AHWageningenThe Netherlands
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Radulescu CI, Garcia-Miralles M, Sidik H, Bardile CF, Yusof NABM, Lee HU, Ho EXP, Chu CW, Layton E, Low D, De Sessions PF, Pettersson S, Ginhoux F, Pouladi MA. Manipulation of microbiota reveals altered callosal myelination and white matter plasticity in a model of Huntington disease. Neurobiol Dis 2019; 127:65-75. [DOI: 10.1016/j.nbd.2019.02.011] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 02/02/2019] [Accepted: 02/20/2019] [Indexed: 01/08/2023] Open
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Zhang L, Xue Z, Liu Q, Liu Y, Xi S, Cheng Y, Li J, Yan J, Shen Y, Xiao C, Xie Z, Qiu Z, Jiang H. Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN. EBioMedicine 2019; 43:473-486. [PMID: 31060905 PMCID: PMC6562069 DOI: 10.1016/j.ebiom.2019.04.048] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 04/24/2019] [Accepted: 04/24/2019] [Indexed: 11/22/2022] Open
Abstract
Background Exposure to anesthetics during early life may impair cognitive functions. However, the underlying mechanisms remain largely unknown. We set out to determine effects of sevoflurane anesthesia on folate metabolism and myelination in young non-human primates, mice and children. Methods Young rhesus macaque and mice received 2.5 to 3% sevoflurane daily for three days. DNA and RNA sequencing and immunohistochemistry among others were used in the studies. We performed unbiased transcriptome profiling in prefrontal cortex of rhesus macaques and mice after the sevoflurane anesthesia. We constructed a brain blood barrier-crossing AAV-PHP.EB vector to harbor ERMN expression in rescue studies. We measured blood folate levels in children after anesthesia and surgery. Findings We found that thymidylate synthase (TYMS) gene was downregulated after the sevoflurane anesthesia in both rhesus macaque and mice. There was a reduction in blood folate levels in children after the anesthesia and surgery. Combined with transcriptome and genome-wide DNA methylation analysis, we identified that ERMN was the primary target of the disrupted folate metabolism. Myelination was compromised by the anesthesia in the young mice, which was rescued by systematic administration of folic acid or expression of ERMN in the brain through brain-specific delivery of the adeno-associated virus. Moreover, folic acid and expression of ERMN alleviated the cognitive impairment caused by the sevoflurane anesthesia in the mice. Interpretation General anesthesia leads to disrupted folate metabolism and subsequently defects in myelination in the developmental brain, and ERMN is the important target affected by the anesthesia via epigenetic mechanisms.
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Affiliation(s)
- Lei Zhang
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Zhenyu Xue
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Qidong Liu
- Anesthesia and Brain Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Yunbo Liu
- The Institute of Laboratory Animal Science, CAMS & PUMC. Beijing, PR China
| | - Siwei Xi
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Yanyong Cheng
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Jingjie Li
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Jia Yan
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Yuan Shen
- Department of Psychiatry, Anesthesia and Brain Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, PR China
| | - Chong Xiao
- The Institute of Laboratory Animal Science, CAMS & PUMC. Beijing, PR China
| | - Zhongcong Xie
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
| | - Zilong Qiu
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
| | - Hong Jiang
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China.
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Faigle W, Cruciani C, Wolski W, Roschitzki B, Puthenparampil M, Tomas-Ojer P, Sellés-Moreno C, Zeis T, Jelcic I, Schaeren-Wiemers N, Sospedra M, Martin R. Brain Citrullination Patterns and T Cell Reactivity of Cerebrospinal Fluid-Derived CD4 + T Cells in Multiple Sclerosis. Front Immunol 2019; 10:540. [PMID: 31024521 PMCID: PMC6467957 DOI: 10.3389/fimmu.2019.00540] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 02/27/2019] [Indexed: 01/11/2023] Open
Abstract
Immune responses to citrullinated peptides have been described in autoimmune diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). We investigated the post-translational modification (PTM), arginine to citrulline, in brain tissue of MS patients and controls (C) by proteomics and subsequently the cellular immune response of cerebrospinal fluid (CSF)-infiltrating T cells to citrullinated and unmodified peptides of myelin basic protein (MBP). Using specifically adapted tissue extraction- and combined data interpretation protocols we could establish a map of citrullinated proteins by identifying more than 80 proteins with two or more citrullinated peptides in human brain tissue. We report many of them for the first time. For the already described citrullinated proteins MBP, GFAP, and vimentin, we could identify additional citrullinated sites. The number of modified proteins in MS white matter was higher than control tissue. Citrullinated peptides are considered neoepitopes that may trigger autoreactivity. We used newly identified epitopes and previously reported immunodominant myelin peptides in their citrullinated and non-citrullinated form to address the recognition of CSF-infiltrating CD4+ T cells from 22 MS patients by measuring proliferation and IFN-γ secretion. We did not detect marked responses to citrullinated peptides, but slightly more strongly to the non-modified version. Based on these data, we conclude that citrullination does not appear to be an important activating factor of a T cell response, but could be the consequence of an immune- or inflammatory response. Our approach allowed us to perform a deep proteome analysis and opens new technical possibilities to analyze complex PTM patterns on minute quantities of rare tissue samples.
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Affiliation(s)
- Wolfgang Faigle
- Neuroimmunology and MS Research Section, Neurology Clinic, University Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Carolina Cruciani
- Neuroimmunology and MS Research Section, Neurology Clinic, University Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Witold Wolski
- Functional Genomics Center Zurich, ETH Zurich & University of Zurich, Zurich, Switzerland
| | - Bernd Roschitzki
- Functional Genomics Center Zurich, ETH Zurich & University of Zurich, Zurich, Switzerland
| | - Marco Puthenparampil
- Neuroimmunology and MS Research Section, Neurology Clinic, University Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Paula Tomas-Ojer
- Neuroimmunology and MS Research Section, Neurology Clinic, University Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Carla Sellés-Moreno
- Neuroimmunology and MS Research Section, Neurology Clinic, University Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Thomas Zeis
- Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Ivan Jelcic
- Neuroimmunology and MS Research Section, Neurology Clinic, University Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Nicole Schaeren-Wiemers
- Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Mireia Sospedra
- Neuroimmunology and MS Research Section, Neurology Clinic, University Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Roland Martin
- Neuroimmunology and MS Research Section, Neurology Clinic, University Zurich, University Hospital Zurich, Zurich, Switzerland
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45
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Seixas AI, Azevedo MM, Paes de Faria J, Fernandes D, Mendes Pinto I, Relvas JB. Evolvability of the actin cytoskeleton in oligodendrocytes during central nervous system development and aging. Cell Mol Life Sci 2019; 76:1-11. [PMID: 30302529 PMCID: PMC11105620 DOI: 10.1007/s00018-018-2915-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 08/24/2018] [Accepted: 09/04/2018] [Indexed: 01/23/2023]
Abstract
The organization of actin filaments into a wide range of subcellular structures is a defining feature of cell shape and dynamics, important for tissue development and homeostasis. Nervous system function requires morphological and functional plasticity of neurons and glial cells, which is largely determined by the dynamic reorganization of the actin cytoskeleton in response to intrinsic and extracellular signals. Oligodendrocytes are specialized glia that extend multiple actin-based protrusions to form the multilayered myelin membrane that spirally wraps around axons, increasing conduction speed and promoting long-term axonal integrity. Myelination is a remarkable biological paradigm in development, and maintenance of myelin is essential for a healthy adult nervous system. In this review, we discuss how structure and dynamics of the actin cytoskeleton is a defining feature of myelinating oligodendrocytes' biology and function. We also review "old and new" concepts to reflect on the potential role of the cytoskeleton in balancing life and death of myelin membranes and oligodendrocytes in the aging central nervous system.
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Affiliation(s)
- Ana Isabel Seixas
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.
- IBMC - Instituto de Biologia Molecular e Celular, Porto, Portugal.
| | - Maria Manuela Azevedo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IBMC - Instituto de Biologia Molecular e Celular, Porto, Portugal
| | - Joana Paes de Faria
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IBMC - Instituto de Biologia Molecular e Celular, Porto, Portugal
| | - Diogo Fernandes
- Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- International Iberian Nanotechnology Laboratory - INL, Braga, Portugal
| | - Inês Mendes Pinto
- International Iberian Nanotechnology Laboratory - INL, Braga, Portugal
| | - João Bettencourt Relvas
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IBMC - Instituto de Biologia Molecular e Celular, Porto, Portugal
- The Discoveries Centre for Regeneration and Precision Medicine, Porto Campus, Porto, Portugal
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Elazar N, Vainshtein A, Golan N, Vijayaragavan B, Schaeren-Wiemers N, Eshed-Eisenbach Y, Peles E. Axoglial Adhesion by Cadm4 Regulates CNS Myelination. Neuron 2018; 101:224-231.e5. [PMID: 30551998 DOI: 10.1016/j.neuron.2018.11.032] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/03/2018] [Accepted: 11/16/2018] [Indexed: 10/27/2022]
Abstract
The initiation of axoglial contact is considered a prerequisite for myelination, yet the role cell adhesion molecules (CAMs) play in mediating such interactions remains unclear. To examine the function of axoglial CAMs, we tested whether enhanced CAM-mediated adhesion between OLs and neurons could affect myelination. Here we show that increased expression of a membrane-bound extracellular domain of Cadm4 (Cadm4dCT) in cultured oligodendrocytes results in the production of numerous axoglial contact sites that fail to elongate and generate mature myelin. Transgenic mice expressing Cadm4dCT were hypomyelinated and exhibit multiple myelin abnormalities, including myelination of neuronal somata. These abnormalities depend on specific neuron-glial interaction as they were not observed when these OLs were cultured alone, on nanofibers, or on neurons isolated from mice lacking the axonal receptors of Cadm4. Our results demonstrate that tightly regulated axon-glia adhesion is essential for proper myelin targeting and subsequent membrane wrapping and lateral extension.
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Affiliation(s)
- Nimrod Elazar
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
| | - Anya Vainshtein
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
| | - Neev Golan
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
| | - Bharath Vijayaragavan
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
| | | | - Yael Eshed-Eisenbach
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
| | - Elior Peles
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
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Donkels C, Pfeifer D, Janz P, Huber S, Nakagawa J, Prinz M, Schulze-Bonhage A, Weyerbrock A, Zentner J, Haas CA. Whole Transcriptome Screening Reveals Myelination Deficits in Dysplastic Human Temporal Neocortex. Cereb Cortex 2018; 27:1558-1572. [PMID: 26796214 DOI: 10.1093/cercor/bhv346] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Focal cortical dysplasias (FCDs) are local malformations of the human neocortex with strong epileptogenic potential. To investigate the underlying pathomechanisms, we performed a whole human transcriptome screening to compare the gene expression pattern of dysplastic versus nondysplastic temporal neocortex. Tissue obtained from FCD IIIa cases (mean age 20.5 years) who had undergone surgical treatment, due to intractable epilepsy, was compared with nondysplastic specimens (mean age 19.9 years) by means of Affymetrix arrays covering 28 869 genes. We found 211 differentially expressed genes (DEX) among which mainly genes important for oligodendrocyte differentiation and myelination were downregulated in FCD IIIa. These findings were confirmed as functionally important by Database for Annotation, Visualization, and Integrated Discovery (DAVID) analysis. The reduced expression of myelin-associated transcripts was confirmed for FCD Ia, IIa, and IIIa by real-time RT-qPCR. In addition, we found that the density of myelin basic protein mRNA-expressing oligodendrocytes and of 2',3'-cyclic nucleotide 3'-phosphodiesterase-positive myelin fibers was significantly reduced in dysplastic cortex. Moreover, high-resolution confocal imaging and 3D reconstruction revealed that the myelin fiber network was severely disorganized in dysplastic neocortex, indicating a disturbance of myelin sheath formation and maintenance in FCD.
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Affiliation(s)
- Catharina Donkels
- Experimental Epilepsy Research, Department of Neurosurgery.,Faculty of Biology
| | - Dietmar Pfeifer
- Department of Hematology, Oncology and Stem Cell Transplantation
| | - Philipp Janz
- Experimental Epilepsy Research, Department of Neurosurgery.,Faculty of Biology
| | - Susanne Huber
- Experimental Epilepsy Research, Department of Neurosurgery
| | - Julia Nakagawa
- Experimental Epilepsy Research, Department of Neurosurgery.,Department of Neurosurgery
| | - Marco Prinz
- Institute of Neuropathology.,Center for Biological Signalling Studies
| | - Andreas Schulze-Bonhage
- Epilepsy Center Freiburg, University Medical Center Freiburg, Freiburg, Germany.,BrainLinks-BrainTools, University of Freiburg, Freiburg, Germany
| | | | | | - Carola A Haas
- Experimental Epilepsy Research, Department of Neurosurgery.,Bernstein Center Freiburg.,BrainLinks-BrainTools, University of Freiburg, Freiburg, Germany
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48
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Single-cell transcriptomics of the developing lateral geniculate nucleus reveals insights into circuit assembly and refinement. Proc Natl Acad Sci U S A 2018; 115:E1051-E1060. [PMID: 29343640 PMCID: PMC5798372 DOI: 10.1073/pnas.1717871115] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Neurons and nonneuronal cells in the developing brain dynamically regulate gene expression as neural connectivity is established. However, the specific gene programs activated in distinct cell populations during the assembly and refinement of many intact neuronal circuits have not been thoroughly characterized. In this study, we take advantage of recent advances in transcriptomic profiling techniques to characterize gene expression in the postnatal developing lateral geniculate nucleus (LGN) at single-cell resolution. Our data reveal that genes involved in brain development are dynamically regulated in all major cell types of the LGN, suggesting that the establishment of neural connectivity depends upon functional collaboration between multiple neuronal and nonneuronal cell types in this brain region. Coordinated changes in gene expression underlie the early patterning and cell-type specification of the central nervous system. However, much less is known about how such changes contribute to later stages of circuit assembly and refinement. In this study, we employ single-cell RNA sequencing to develop a detailed, whole-transcriptome resource of gene expression across four time points in the developing dorsal lateral geniculate nucleus (LGN), a visual structure in the brain that undergoes a well-characterized program of postnatal circuit development. This approach identifies markers defining the major LGN cell types, including excitatory relay neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells. Most cell types exhibit significant transcriptional changes across development, dynamically expressing genes involved in distinct processes including retinotopic mapping, synaptogenesis, myelination, and synaptic refinement. Our data suggest that genes associated with synapse and circuit development are expressed in a larger proportion of nonneuronal cell types than previously appreciated. Furthermore, we used this single-cell expression atlas to identify the Prkcd-Cre mouse line as a tool for selective manipulation of relay neurons during a late stage of sensory-driven synaptic refinement. This transcriptomic resource provides a cellular map of gene expression across several cell types of the LGN, and offers insight into the molecular mechanisms of circuit development in the postnatal brain.
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Liang F. Olfactory receptor neuronal dendrites become mostly intra-sustentacularly enwrapped upon maturity. J Anat 2018; 232:674-685. [PMID: 29313978 DOI: 10.1111/joa.12777] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2017] [Indexed: 10/18/2022] Open
Abstract
The mammalian olfactory epithelium (OE) sustains persistent neurogenesis even in the adult. Sustentacular cells therein play both epithelial and neuroglial roles, although their relation with olfactory receptor neurons (ORNs) and their function in ORN maturation remain insufficiently understood. Sustentacular wrapping of ORN dendrites has been long known but always considered a minor presence, as opposed to the supposedly unwrapped majority of ORN dendrites at inter-sustentacular borderlines. Using immunofluorescence, confocal and immuno-electron microscopy, the current study examined cytoarchitectonic organization and maturation of ORN dendrites at the rat OE apical layer. Contrary to common belief, the observations here on tangential histological sections of the OE apical junctional belt layer showed on average 53.93% sustentacular cell-enwrapped, 18.46% partially wrapped (in the vertical grooves on the sides of sustentacular apices) and 27.61% unwrapped ORN dendrites (at the borderlines between sustentacular cells). The enwrapped dendrites were found within the confines of sustentacular apices but linked to the sides of the latter each by a mesentery (mesodendrite) of sustentacular plasma membranes and autotypic cell junctions. Up to six dendrites were seen in one sustentacular apical process. As marked by high and low immunoreactivity for class III beta-tubulin, respectively, immature and mature ORN dendrites accounted on average for 12.46 and 87.54% of the total ORN dendrites at the OE apical layer. By correlative analysis of the maturity level and wrapping status, most immature ORN dendrites were found unwrapped (immature unwrapped = 9.71% of the total dendrites), and practically no immature dendrites appeared enwrapped. In contrast, mature ORN dendrites comprised all the enwrapped (mature enwrapped = 53.93% of the total), most of the partially wrapped (mature partially wrapped = 15.71% of the total) and a portion of the unwrapped ORN dendrites (mature unwrapped = 17.9% of the total dendrites). Based on the current findings and previous data by other researchers, it is concluded that immature ORN dendrites emerge vertically from the OE apical surface between sustentacular cell apices. A large majority of the newly emerged dendrites then undergo sideways migration, sustentacular enwrapment and further maturation. Only a small minority of the newly emerged dendrites reach maturity and remain unwrapped. These divergent maturational courses imply structural or functional differences between the enwrapped and unwrapped mature ORN dendrites.
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Affiliation(s)
- Fengyi Liang
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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50
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Zhao D, Lin M, Pedrosa E, Lachman HM, Zheng D. Characteristics of allelic gene expression in human brain cells from single-cell RNA-seq data analysis. BMC Genomics 2017; 18:860. [PMID: 29126398 PMCID: PMC5681780 DOI: 10.1186/s12864-017-4261-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 11/01/2017] [Indexed: 12/24/2022] Open
Abstract
Background Monoallelic expression of autosomal genes has been implicated in human psychiatric disorders. However, there is a paucity of allelic expression studies in human brain cells at the single cell and genome wide levels. Results In this report, we reanalyzed a previously published single-cell RNA-seq dataset from several postmortem human brains and observed pervasive monoallelic expression in individual cells, largely in a random manner. Examining single nucleotide variants with a predicted functional disruption, we found that the “damaged” alleles were overall expressed in fewer brain cells than their counterparts, and at a lower level in cells where their expression was detected. We also identified many brain cell type-specific monoallelically expressed genes. Interestingly, many of these cell type-specific monoallelically expressed genes were enriched for functions important for those brain cell types. In addition, function analysis showed that genes displaying monoallelic expression and correlated expression across neuronal cells from different individual brains were implicated in the regulation of synaptic function. Conclusions Our findings suggest that monoallelic gene expression is prevalent in human brain cells, which may play a role in generating cellular identity and neuronal diversity and thus increasing the complexity and diversity of brain cell functions. Electronic supplementary material The online version of this article (10.1186/s12864-017-4261-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dejian Zhao
- Department of Neurology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.,Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA
| | - Mingyan Lin
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.,Present address: Department of Neuroscience, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu, 21166, China
| | - Erika Pedrosa
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA
| | - Herbert M Lachman
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.,Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.,Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.,Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA
| | - Deyou Zheng
- Department of Neurology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA. .,Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA. .,Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.
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