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Wang L, Li W, Wu W, Liu Q, You M, Liu X, Ye C, Chen J, Tan Q, Liu G, Du Y. Effects of electroacupuncture on microglia phenotype and epigenetic modulation of C/EBPβ in SAMP8 mice. Brain Res 2025; 1849:149339. [PMID: 39577714 DOI: 10.1016/j.brainres.2024.149339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 11/13/2024] [Accepted: 11/15/2024] [Indexed: 11/24/2024]
Abstract
BACKGROUND Alzheimer's disease (AD), an age-progressive neurodegenerative disease, is featured by a relentless deterioration of cognitive abilities. In parallel with the hypotheses of Aβ and tau, microglia-mediated neuroinflammation is a core pathological hallmark of AD. Promoting the transition of microglia from M1 to M2 phenotype and inhibition of neuroinflammatory response provide new insights into the treatment of AD. And substantial studies have confirmed that overexpression of C/EBPβ accelerates the progression of AD pathology. Acupuncture is renowned for its unique advantages including safety and effectiveness, which has gained wide application in geriatric diseases, and thoroughly exploring the mechanism for its treatment of AD will provide scientific basis for its clinical application. METHODS In this study, SAMP8 mice were employed and EA therapy was performed as the main intervention. The combination of behavioural experiments (including water maze and novel objective recognition), Immunofluorescence, Western blot, and Chip-qPCR assay were performed to compare between different groups. RESULTS EA therapy facilitates the polarization of microglia from M1 to M2 phenotype, reduces pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and promotes the expression of anti-inflammatory factors (IL-4 and IL-10), as well as attenuates neuroinflammation. Simultaneously, EA also inhibits the enrichment of H3K9ac at C/EBPβ promoter region and expression of C/EBPβ. Thus, it was evident that EA had a favorable effect on ameliorating cognitive decline in SAMP8 mice. CONCLUSION EA therapy may ameliorate cognitive deficits in AD via facilitating microglia shift from M1 to M2 phenotype and epigenetically regulating C/EBPβ. And further studies are required to better understand how the mechanism between microglia and epigenetic modulation of C/EBPβ are effective in reversing AD.
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Affiliation(s)
- Li Wang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China; Hubei Shizhen Laboratory, Wuhan, Hubei, China.
| | - Weixian Li
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Wenhui Wu
- Department of Rehabilitation Medicine, Central Theater General Hospital of the Chinese People's Liberation Army, Wuhan, Hubei, China
| | - Qing Liu
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Min You
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Xinyuan Liu
- Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Cheng Ye
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Jiangmin Chen
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Qian Tan
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Guangya Liu
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Yanjun Du
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China; Hubei Shizhen Laboratory, Wuhan, Hubei, China; Affiliated Hospital of Hubei University of Chinese Medicine (Hubei Provincial Hospital of Traditional Chinese Medicine), Wuhan, Hubei, China.
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Sasikumar DSN, Thiruselvam P, Sundararajan V, Ravindran R, Gunasekaran S, Madathil D, Kaliamurthi S, Peslherbe GH, Selvaraj G, Sudhakaran SL. Insights into dietary phytochemicals targeting Parkinson's disease key genes and pathways: A network pharmacology approach. Comput Biol Med 2024; 172:108195. [PMID: 38460310 DOI: 10.1016/j.compbiomed.2024.108195] [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: 09/03/2023] [Revised: 01/26/2024] [Accepted: 02/18/2024] [Indexed: 03/11/2024]
Abstract
Parkinson's disease (PD) is a complex neurological disease associated with the degeneration of dopaminergic neurons. Oxidative stress is a key player in instigating apoptosis in dopaminergic neurons. To improve the survival of neurons many dietary phytochemicals have gathered significant attention recently. Thus, the present study implements a comprehensive network pharmacology approach to unravel the mechanisms of action of dietary phytochemicals that benefit disease management. A literature search was performed to identify ligands (i.e., comprising dietary phytochemicals and Food and Drug Administration pre-approved PD drugs) in the PubMed database. Targets associated with selected ligands were extracted from the search tool for interactions of chemicals (STITCH) database. Then, the construction of a gene-gene interaction (GGI) network, analysis of hub-gene, functional and pathway enrichment, associated transcription factors, miRNAs, ligand-target interaction network, docking were performed using various bioinformatics tools together with molecular dynamics (MD) simulations. The database search resulted in 69 ligands and 144 unique targets. GGI and subsequent topological measures indicate histone acetyltransferase p300 (EP300), mitogen-activated protein kinase 1 (MAPK1) or extracellular signal-regulated kinase (ERK)2, and CREB-binding protein (CREBBP) as hub genes. Neurodegeneration, MAPK signaling, apoptosis, and zinc binding are key pathways and gene ontology terms. hsa-miR-5692a and SCNA gene-associated transcription factors interact with all the 3 hub genes. Ligand-target interaction (LTI) network analysis suggest rasagiline and baicalein as candidate ligands targeting MAPK1. Rasagiline and baicalein form stable complexes with the Y205, K330, and V173 residues of MAPK1. Computational molecular insights suggest that baicalein and rasagiline are promising preclinical candidates for PD management.
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Affiliation(s)
- Devi Soorya Narayana Sasikumar
- Integrative Multiomics Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, TN, 632014, India
| | - Premkumar Thiruselvam
- Integrative Multiomics Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, TN, 632014, India
| | - Vino Sundararajan
- Integrative Multiomics Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, TN, 632014, India
| | - Radhika Ravindran
- Department of Biotechnology, Indian Institute of Technology (Madras), Chennai, TN, 600036, India
| | - Shoba Gunasekaran
- Department of Biotechnology, Dwaraka Doss Goverdhan Doss Vaishnav College, Chennai, TN, 600106, India
| | - Deepa Madathil
- Jindal Institute of Behavioral Sciences, O.P Jindal Global University, Sonipat, Haryana, 131001, India
| | - Satyavani Kaliamurthi
- Centre for Research in Molecular Modeling (CERMM), Department of Chemistry and Biochemistry, Concordia University, Loyola Campus, Montreal, QC, H4B 1R6, Canada
| | - Gilles H Peslherbe
- Centre for Research in Molecular Modeling (CERMM), Department of Chemistry and Biochemistry, Concordia University, Loyola Campus, Montreal, QC, H4B 1R6, Canada
| | - Gurudeeban Selvaraj
- Centre for Research in Molecular Modeling (CERMM), Department of Chemistry and Biochemistry, Concordia University, Loyola Campus, Montreal, QC, H4B 1R6, Canada; Bioinformatics Unit, Department of Biomaterials, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS) University, Chennai, TN, 600077, India.
| | - Sajitha Lulu Sudhakaran
- Integrative Multiomics Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, TN, 632014, India.
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Miranda P, Mirisis AA, Kukushkin NV, Carew TJ. Pattern detection in the TGFβ cascade controls the induction of long-term synaptic plasticity. Proc Natl Acad Sci U S A 2023; 120:e2300595120. [PMID: 37748056 PMCID: PMC10556637 DOI: 10.1073/pnas.2300595120] [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: 01/13/2023] [Accepted: 08/11/2023] [Indexed: 09/27/2023] Open
Abstract
Transforming growth factor β (TGFβ) is required for long-term memory (LTM) for sensitization in Aplysia. When LTM is induced using a two-trial training protocol, TGFβ inhibition only blocks LTM when administrated at the second, not the first trial. Here, we show that TGFβ acts as a "repetition detector" during the induction of two-trial LTM. Secretion of the biologically inert TGFβ proligand must coincide with its proteolytic activation by the Bone morphogenetic protein-1 (BMP-1/Tolloid) metalloprotease, which occurs specifically during trial two of our two-trial training paradigm. This paradigm establishes long-term synaptic facilitation (LTF), the cellular correlate of LTM. BMP-1 application paired with a single serotonin (5HT) pulse induced LTF, whereas neither a single 5HT pulse nor BMP-1 alone effectively did so. On the other hand, inhibition of endogenous BMP-1 activity blocked the induction of two-trial LTF. These results suggest a unique role for TGFβ in the interaction of repeated trials: during learning, repeated stimuli engage separate steps of the TGFβ cascade that together are necessary for the induction of long-lasting memories.
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Affiliation(s)
- Paige Miranda
- Center for Neural Science, New York University, New York, NY10003
| | | | - Nikolay V. Kukushkin
- Center for Neural Science, New York University, New York, NY10003
- Liberal Studies, New York University, New York, NY10003
| | - Thomas J. Carew
- Center for Neural Science, New York University, New York, NY10003
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Di Liegro CM, Schiera G, Schirò G, Di Liegro I. Involvement of the H3.3 Histone Variant in the Epigenetic Regulation of Gene Expression in the Nervous System, in Both Physiological and Pathological Conditions. Int J Mol Sci 2023; 24:11028. [PMID: 37446205 DOI: 10.3390/ijms241311028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/19/2023] [Accepted: 07/01/2023] [Indexed: 07/15/2023] Open
Abstract
All the cells of an organism contain the same genome. However, each cell expresses only a minor fraction of its potential and, in particular, the genes encoding the proteins necessary for basal metabolism and the proteins responsible for its specific phenotype. The ability to use only the right and necessary genes involved in specific functions depends on the structural organization of the nuclear chromatin, which in turn depends on the epigenetic history of each cell, which is stored in the form of a collection of DNA and protein modifications. Among these modifications, DNA methylation and many kinds of post-translational modifications of histones play a key role in organizing the complex indexing of usable genes. In addition, non-canonical histone proteins (also known as histone variants), the synthesis of which is not directly linked with DNA replication, are used to mark specific regions of the genome. Here, we will discuss the role of the H3.3 histone variant, with particular attention to its loading into chromatin in the mammalian nervous system, both in physiological and pathological conditions. Indeed, chromatin modifications that mark cell memory seem to be of special importance for the cells involved in the complex processes of learning and memory.
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Affiliation(s)
- Carlo Maria Di Liegro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy
| | - Gabriella Schiera
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy
| | - Giuseppe Schirò
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Bi.N.D.), University of Palermo, 90127 Palermo, Italy
| | - Italia Di Liegro
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Bi.N.D.), University of Palermo, 90127 Palermo, Italy
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Kabir F, Atkinson R, Cook AL, Phipps AJ, King AE. The role of altered protein acetylation in neurodegenerative disease. Front Aging Neurosci 2023; 14:1025473. [PMID: 36688174 PMCID: PMC9845957 DOI: 10.3389/fnagi.2022.1025473] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/03/2022] [Indexed: 01/06/2023] Open
Abstract
Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.
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Kumar R, Fatima F, Yadav G, Singh S, Haldar S, Alexiou A, Ashraf GM. Epigenetic Modifications by Estrogen and Androgen in Alzheimer's Disease. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2023; 22:6-17. [PMID: 35232367 DOI: 10.2174/1871527321666220225110501] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 01/17/2022] [Accepted: 01/17/2022] [Indexed: 12/16/2022]
Abstract
For the development and maintenance of neuron networks in the brain, epigenetic mechanisms are necessary, as indicated by recent findings. This includes some of the high-order brain processes, such as behavior and cognitive functions. Epigenetic mechanisms could influence the pathophysiology or etiology of some neuronal diseases, altering disease susceptibility and therapy responses. Recent studies support epigenetic dysfunctions in neurodegenerative and psychiatric conditions, such as Alzheimer's disease (AD). These dysfunctions in epigenetic mechanisms also play crucial roles in the transgenerational effects of the environment on the brain and subsequently in the inheritance of pathologies. The possible role of gonadal steroids in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, has become the subject of a growing body of research over the last 20 years. Recent scientific findings suggest that epigenetic changes, driven by estrogen and androgens, play a vital role in brain functioning. Therefore, exploring the role of estrogen and androgen-based epigenetic changes in the brain is critical for the deeper understanding of AD. This review highlights the epigenetic modifications caused by these two gonadal steroids and the possible therapeutic strategies for AD.
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Affiliation(s)
- Rajnish Kumar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Uttar Pradesh, India
| | - Faiza Fatima
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Uttar Pradesh, India
| | - Garima Yadav
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Uttar Pradesh, India
| | - Simran Singh
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Uttar Pradesh, India
| | - Subhagata Haldar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Uttar Pradesh, India
| | - Athanasios Alexiou
- Novel Global Community Educational Foundation, Hebersham, 2770 NSW, Australia, and AFNP Med Austria, 1010 Wien, Austria
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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7
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deAndrés-Galiana EJ, Fernández-Martínez JL, Álvarez-Machancoses Ó, Bea G, Galmarini CM, Kloczkowski A. Analysis of transcriptomic responses to SARS-CoV-2 reveals plausible defective pathways responsible for increased susceptibility to infection and complications and helps to develop fast-track repositioning of drugs against COVID-19. Comput Biol Med 2022; 149:106029. [PMID: 36067633 PMCID: PMC9423878 DOI: 10.1016/j.compbiomed.2022.106029] [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: 04/20/2022] [Revised: 07/08/2022] [Accepted: 08/20/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND To understand the transcriptomic response to SARS-CoV-2 infection, is of the utmost importance to design diagnostic tools predicting the severity of the infection. METHODS We have performed a deep sampling analysis of the viral transcriptomic data oriented towards drug repositioning. Using different samplers, the basic principle of this methodology the biological invariance, which means that the pathways altered by the disease, should be independent on the algorithm used to unravel them. RESULTS The transcriptomic analysis of the altered pathways, reveals a distinctive inflammatory response and potential side effects of infection. The virus replication causes, in some cases, acute respiratory distress syndrome in the lungs, and affects other organs such as heart, brain, and kidneys. Therefore, the repositioned drugs to fight COVID-19 should, not only target the interferon signalling pathway and the control of the inflammation, but also the altered genetic pathways related to the side effects of infection. We also show via Principal Component Analysis that the transcriptome signatures are different from influenza and RSV. The gene COL1A1, which controls collagen production, seems to play a key/vital role in the regulation of the immune system. Additionally, other small-scale signature genes appear to be involved in the development of other COVID-19 comorbidities. CONCLUSIONS Transcriptome-based drug repositioning offers possible fast-track antiviral therapy for COVID-19 patients. It calls for additional clinical studies using FDA approved drugs for patients with increased susceptibility to infection and with serious medical complications.
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Affiliation(s)
- Enrique J deAndrés-Galiana
- Group of Inverse Problems, Optimization and Machine Learning. Department of Mathematics, University of Oviedo, C. Federico García Lorca, 18, 33007, Oviedo, Spain; Department of Computer Science, University of Oviedo, C. Federico García Lorca, 18, 33007, Oviedo, Spain.
| | - Juan Luis Fernández-Martínez
- Group of Inverse Problems, Optimization and Machine Learning. Department of Mathematics, University of Oviedo, C. Federico García Lorca, 18, 33007, Oviedo, Spain; DeepBioInsights, Spain.
| | - Óscar Álvarez-Machancoses
- Group of Inverse Problems, Optimization and Machine Learning. Department of Mathematics, University of Oviedo, C. Federico García Lorca, 18, 33007, Oviedo, Spain.
| | - Guillermina Bea
- Group of Inverse Problems, Optimization and Machine Learning. Department of Mathematics, University of Oviedo, C. Federico García Lorca, 18, 33007, Oviedo, Spain; DeepBioInsights, Spain.
| | - Carlos M Galmarini
- Topazium Artificial Intelligence, Paseo de la Castellana 40, 28046, Madrid, Spain.
| | - Andrzej Kloczkowski
- Battelle Center for Mathematical Medicine, Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
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Gao X, Chen Q, Yao H, Tan J, Liu Z, Zhou Y, Zou Z. Epigenetics in Alzheimer's Disease. Front Aging Neurosci 2022; 14:911635. [PMID: 35813941 PMCID: PMC9260511 DOI: 10.3389/fnagi.2022.911635] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/24/2022] [Indexed: 12/19/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease with unknown pathogenesis and complex pathological manifestations. At present, a large number of studies on targeted drugs for the typical pathological phenomenon of AD (Aβ) have ended in failure. Although there are some drugs on the market that indirectly act on AD, their efficacy is very low and the side effects are substantial, so there is an urgent need to develop a new strategy for the treatment of AD. An increasing number of studies have confirmed epigenetic changes in AD. Although it is not clear whether these epigenetic changes are the cause or result of AD, they provide a new avenue of treatment for medical researchers worldwide. This article summarizes various epigenetic changes in AD, including DNA methylation, histone modification and miRNA, and concludes that epigenetics has great potential as a new target for the treatment of AD.
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Affiliation(s)
- Xiaodie Gao
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
- Department of Scientific Research, Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou, China
| | - Qiang Chen
- Department of Scientific Research, Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou, China
| | - Hua Yao
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
| | - Jie Tan
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
| | - Zheng Liu
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
- *Correspondence: Zheng Liu,
| | - Yan Zhou
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
- Yan Zhou,
| | - Zhenyou Zou
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
- Department of Scientific Research, Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou, China
- Zhenyou Zou,
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Behbahanipour M, García-Pardo J, Ventura S. Decoding the role of coiled-coil motifs in human prion-like proteins. Prion 2021; 15:143-154. [PMID: 34428113 PMCID: PMC8386614 DOI: 10.1080/19336896.2021.1961569] [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: 07/03/2021] [Revised: 07/22/2021] [Accepted: 07/25/2021] [Indexed: 11/28/2022] Open
Abstract
Prions are self-propagating proteins that cause fatal neurodegenerative diseases in humans. However, increasing evidence suggests that eukaryotic cells exploit prion conformational conversion for functional purposes. A recent study delineated a group of twenty prion-like proteins in humans, characterized by the presence of low-complexity glutamine-rich sequences with overlapping coiled-coil (CCs) motifs. This is the case of Mediator complex subunit 15 (MED15), which is overexpressed in a wide range of human cancers. Biophysical studies demonstrated that the prion-like domain (PrLD) of MED15 forms homodimers in solution, sustained by CCs interactions. Furthermore, the same coiled-coil (CC) region plays a crucial role in the PrLD structural transition to a transmissible β-sheet amyloid state. In this review, we discuss the role of CCs motifs and their contribution to amyloid transitions in human prion-like domains (PrLDs), while providing a comprehensive overview of six predicted human prion-like proteins involved in transcription, gene expression, or DNA damage response and associated with human disease, whose PrLDs contain or overlap with CCs sequences. Finally, we try to rationalize how these molecular signatures might relate to both their function and involvement in disease.
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Affiliation(s)
- Molood Behbahanipour
- Institut De Biotecnologia I De Biomedicina (Ibb) and Departament De Bioquímica I Biologia Molecular, Universitat Autónoma De Barcelona, Barcelona, Spain
| | - Javier García-Pardo
- Institut De Biotecnologia I De Biomedicina (Ibb) and Departament De Bioquímica I Biologia Molecular, Universitat Autónoma De Barcelona, Barcelona, Spain
| | - Salvador Ventura
- Institut De Biotecnologia I De Biomedicina (Ibb) and Departament De Bioquímica I Biologia Molecular, Universitat Autónoma De Barcelona, Barcelona, Spain
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10
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Dobrowolny G, Barbiera A, Sica G, Scicchitano BM. Age-Related Alterations at Neuromuscular Junction: Role of Oxidative Stress and Epigenetic Modifications. Cells 2021; 10:1307. [PMID: 34074012 PMCID: PMC8225025 DOI: 10.3390/cells10061307] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/19/2021] [Accepted: 05/22/2021] [Indexed: 12/11/2022] Open
Abstract
With advancing aging, a decline in physical abilities occurs, leading to reduced mobility and loss of independence. Although many factors contribute to the physio-pathological effects of aging, an important event seems to be related to the compromised integrity of the neuromuscular system, which connects the brain and skeletal muscles via motoneurons and the neuromuscular junctions (NMJs). NMJs undergo severe functional, morphological, and molecular alterations during aging and ultimately degenerate. The effect of this decline is an inexorable decrease in skeletal muscle mass and strength, a condition generally known as sarcopenia. Moreover, several studies have highlighted how the age-related alteration of reactive oxygen species (ROS) homeostasis can contribute to changes in the neuromuscular junction morphology and stability, leading to the reduction in fiber number and innervation. Increasing evidence supports the involvement of epigenetic modifications in age-dependent alterations of the NMJ. In particular, DNA methylation, histone modifications, and miRNA-dependent gene expression represent the major epigenetic mechanisms that play a crucial role in NMJ remodeling. It is established that environmental and lifestyle factors, such as physical exercise and nutrition that are susceptible to change during aging, can modulate epigenetic phenomena and attenuate the age-related NMJs changes. This review aims to highlight the recent epigenetic findings related to the NMJ dysregulation during aging and the role of physical activity and nutrition as possible interventions to attenuate or delay the age-related decline in the neuromuscular system.
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Affiliation(s)
- Gabriella Dobrowolny
- Department of Anatomy, Histology, Forensic Medicine and Orthopaedics (DAHFMO)-Unit of Histology and Medical Embryology, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy;
| | - Alessandra Barbiera
- Department of Life Sciences and Public Health, Histology and Embryology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (A.B.); (G.S.)
| | - Gigliola Sica
- Department of Life Sciences and Public Health, Histology and Embryology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (A.B.); (G.S.)
| | - Bianca Maria Scicchitano
- Department of Life Sciences and Public Health, Histology and Embryology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (A.B.); (G.S.)
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Ding L, Wen Y, Zhang X, Zhao F, Lv K, Shi JH, Shen S, Pan X. Transcriptional network constituted of CBP, Ku70, NOX2, and BAX prevents the cell death of necrosis, paraptosis, and apoptosis in human melanoma. Cell Death Discov 2021; 7:40. [PMID: 33637687 PMCID: PMC7910564 DOI: 10.1038/s41420-021-00417-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 01/03/2021] [Accepted: 02/03/2021] [Indexed: 11/20/2022] Open
Abstract
CREB-binding protein (CBP) is an acetyltransferase known to play multiple roles in the transcriptions of genes involving oxidative metabolism, cell cycle, DNA damage checkpoints, and cell death. In this study, CBP was found to positively regulate the expression of Ku70, and both CBP and Ku70 were found to negatively regulate the expression of NOX2, therefore, mitigating the intracellular ROS in human melanoma. Knocking down CBP or Ku70 induced necrotic and paraptotic cell death as indicated by high-level intracellular ROS, cytoplasmic vacuolization, and cell cycle arrest in the S phase. In addition, chromosomal condensations were also observed in the cells proceeding necrotic and paraptotic cell death, which was found to be related to the BAX-associated intrinsic pathway of apoptotic cell death, when Ku70 was decreased either by CBP depletion or by Ku70 depletion directly. Our results, therefore, supported the idea that CBP, Ku70, BAX, and NOX2 have formed a transcriptional network in the prevention of cell death of necrosis, paraptosis, and apoptosis in human melanoma.
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Affiliation(s)
- Liang Ding
- School of Medicine, Hebei University, Baoding, 071002, China
| | - Yalei Wen
- School of Medicine, Hebei University, Baoding, 071002, China
| | - Xin Zhang
- School of Medicine, Hebei University, Baoding, 071002, China
| | - Fang Zhao
- School of Medicine, Hebei University, Baoding, 071002, China
| | - Kenao Lv
- School of Life Science, Beijing Institute of Technology, Beijin, 100081, China
| | - Jian-Hong Shi
- Central Laboratory, Affiliated Hospital of Hebei University, Baoding, 071002, China
| | - Shigang Shen
- School of Chemistry and environmental Science, Hebei University, Baodin, 071002, China
| | - Xuefeng Pan
- School of Medicine, Hebei University, Baoding, 071002, China. .,School of Life Science, Beijing Institute of Technology, Beijin, 100081, China. .,School of Chemistry and environmental Science, Hebei University, Baodin, 071002, China.
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12
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Li Y, Huang H, Zhu M, Bai H, Huang X. Roles of the MYST Family in the Pathogenesis of Alzheimer's Disease via Histone or Non-histone Acetylation. Aging Dis 2021; 12:132-142. [PMID: 33532133 PMCID: PMC7801277 DOI: 10.14336/ad.2020.0329] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Accepted: 03/29/2020] [Indexed: 11/01/2022] Open
Abstract
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and a major cause of death among elderly individuals. The etiology of AD involves a combination of genetic, environmental, and lifestyle factors. A number of epigenetic alterations in AD have recently been reported; for example, studies have found an increase in histone acetylation in patients with AD and the protective function of histone deacetylase inhibitors. The histone acetylases in the MYST family are involved in a number of key nuclear processes, such as gene-specific transcriptional regulation, DNA replication, and DNA damage response. Therefore, it is not surprising that they contribute to epigenetic regulation as an intermediary between genetic and environmental factors. MYST proteins also exert acetylation activity on non-histone proteins that are closely associated with the pathogenesis of AD. In this review, we summarized the current understanding of the roles of MYST acetyltransferases in physiological functions and pathological processes related to AD. Additionally, using published RNA-seq, ChIP-seq, and ChIP-chip data, we identified enriched pathways to further evaluate the correlation between MYST and AD. The recent research described in this review supports the importance of epigenetic modifications and the MYST family in AD, providing a basis for future functional studies.
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Affiliation(s)
- Yuhong Li
- 1State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming, Yunnan, China.,2Yunnan Institute of Tropical Crops, Jinghong, China
| | - Hui Huang
- 1State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming, Yunnan, China
| | - Man Zhu
- 1State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming, Yunnan, China
| | - Hua Bai
- 1State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming, Yunnan, China.,3College of Public Health, Kunming Medical University, Kunming, China
| | - Xiaowei Huang
- 1State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming, Yunnan, China
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13
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Chatterjee S, Angelakos CC, Bahl E, Hawk JD, Gaine ME, Poplawski SG, Schneider-Anthony A, Yadav M, Porcari GS, Cassel JC, Giese KP, Michaelson JJ, Lyons LC, Boutillier AL, Abel T. The CBP KIX domain regulates long-term memory and circadian activity. BMC Biol 2020; 18:155. [PMID: 33121486 PMCID: PMC7597000 DOI: 10.1186/s12915-020-00886-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 10/01/2020] [Indexed: 12/23/2022] Open
Abstract
Background CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors potentially affecting expression of thousands of genes. Identifying specific domain functions for multi-domain proteins is essential to understand processes such as cognitive function and circadian clocks. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. Results We found that CBPKIX/KIX mice were impaired in long-term memory, but not learning acquisition or short-term memory for the Morris water maze. Using an unbiased analysis of gene expression in the dorsal hippocampus after training in the Morris water maze or contextual fear conditioning, we discovered dysregulation of CREB, CLOCK, and BMAL1 target genes and downregulation of circadian genes in CBPKIX/KIX mice. Given our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity and phase resetting in CBPKIX/KIX mice. CBPKIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark. Interestingly, CBPKIX/KIX mice displayed phase delays and advances in response to photic stimulation comparable to wildtype littermates. Thus, this work delineates site-specific regulation of the circadian clock by a multi-domain protein. Conclusions These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms. Graphical abstract ![]()
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Affiliation(s)
- Snehajyoti Chatterjee
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France.,LNCA, CNRS UMR 7364, Strasbourg, France.,Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Christopher C Angelakos
- Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, USA.,Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Ethan Bahl
- Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.,Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, Iowa, USA
| | - Joshua D Hawk
- Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, USA.,Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Marie E Gaine
- Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Shane G Poplawski
- Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, USA.,Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.,Pharmacology Graduate Group, University of Pennsylvania, Philadelphia, USA
| | - Anne Schneider-Anthony
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France.,LNCA, CNRS UMR 7364, Strasbourg, France
| | - Manish Yadav
- Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Giulia S Porcari
- Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Jean-Christophe Cassel
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
| | - K Peter Giese
- Department of Basic and Clinical Neuroscience, King's College London, London, UK
| | - Jacob J Michaelson
- Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.,Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, Iowa, USA.,Department of Communication Sciences and Disorders, College of Liberal Arts and Sciences, University of Iowa, Iowa City, Iowa, USA.,Iowa Institute of Human Genetics, University of Iowa, Iowa City, Iowa, USA
| | - Lisa C Lyons
- Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.,Program in Neuroscience, Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Anne-Laurence Boutillier
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France. .,LNCA, CNRS UMR 7364, Strasbourg, France.
| | - Ted Abel
- Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
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14
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Silva MC, Haggarty SJ. Human pluripotent stem cell-derived models and drug screening in CNS precision medicine. Ann N Y Acad Sci 2020; 1471:18-56. [PMID: 30875083 PMCID: PMC8193821 DOI: 10.1111/nyas.14012] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 01/02/2019] [Accepted: 01/07/2019] [Indexed: 12/12/2022]
Abstract
Development of effective therapeutics for neurological disorders has historically been challenging partly because of lack of accurate model systems in which to investigate disease etiology and test new therapeutics at the preclinical stage. Human stem cells, particularly patient-derived induced pluripotent stem cells (iPSCs) upon differentiation, have the ability to recapitulate aspects of disease pathophysiology and are increasingly recognized as robust scalable systems for drug discovery. We review advances in deriving cellular models of human central nervous system (CNS) disorders using iPSCs along with strategies for investigating disease-relevant phenotypes, translatable biomarkers, and therapeutic targets. Given their potential to identify novel therapeutic targets and leads, we focus on phenotype-based, small-molecule screens employing human stem cell-derived models. Integrated efforts to assemble patient iPSC-derived cell models with deeply annotated clinicopathological data, along with molecular and drug-response signatures, may aid in the stratification of patients, diagnostics, and clinical trial success, shifting translational science and precision medicine approaches. A number of remaining challenges, including the optimization of cost-effective, large-scale culture of iPSC-derived cell types, incorporation of aging into neuronal models, as well as robustness and automation of phenotypic assays to support quantitative drug efficacy, toxicity, and metabolism testing workflows, are covered. Continued advancement of the field is expected to help fully humanize the process of CNS drug discovery.
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Affiliation(s)
- M. Catarina Silva
- Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Center for Genomic Medicine, Harvard Medical School, Boston MA, USA
| | - Stephen J. Haggarty
- Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Center for Genomic Medicine, Harvard Medical School, Boston MA, USA
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15
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Formisano L, Guida N, Mascolo L, Serani A, Laudati G, Pizzorusso V, Annunziato L. Transcriptional and epigenetic regulation of ncx1 and ncx3 in the brain. Cell Calcium 2020; 87:102194. [PMID: 32172011 DOI: 10.1016/j.ceca.2020.102194] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 03/03/2020] [Accepted: 03/04/2020] [Indexed: 01/26/2023]
Abstract
Sodium-calcium exchanger (NCX) 1 and 3, have been demonstrated to play a relevant role in controlling the intracellular homeostasis of sodium and calcium ions in physiological and patho-physiological conditions. While NCX1 and NCX3 knocking-down have been both implicated in brain ischemia, several aspects of the epigenetic regulation of these two antiporters transcription were not yet well characterized. In response to stroke, NCX1 and NCX3 transcriptional regulation occurs from specific promoter sequences. Several evidences have shown that the expression of NCX1 and NCX3 can be determined by epigenetic modifications, consisting in changes of the histone acetylation levels on their promoter sequences. An interesting issue is that histone modifications at the NCX1 and NCX3 promoters could be linked to neurodegeneration occurring after stroke. Therefore, identifying the epigenetic regulation at the NCX1 and NCX3 promoters could permit to identify new molecular targets that can open new strategies for stroke treatment. The current review reassumes the recent knowledge of histone modifications of NCX1 and NCX3 genes in brain in physiological and patho-physiological conditions.
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Affiliation(s)
- Luigi Formisano
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Via Pansini, 5, 80131, Naples, Italy.
| | - Natascia Guida
- IRCCS SDN Naples, Via Emanuele Gianturco 113, 80143, Naples, Italy
| | - Luigi Mascolo
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Via Pansini, 5, 80131, Naples, Italy
| | - Angelo Serani
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Via Pansini, 5, 80131, Naples, Italy
| | - Giusy Laudati
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Via Pansini, 5, 80131, Naples, Italy
| | - Vincenzo Pizzorusso
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Via Pansini, 5, 80131, Naples, Italy
| | - Lucio Annunziato
- IRCCS SDN Naples, Via Emanuele Gianturco 113, 80143, Naples, Italy
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16
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Network-based identification of genetic factors in ageing, lifestyle and type 2 diabetes that influence to the progression of Alzheimer's disease. INFORMATICS IN MEDICINE UNLOCKED 2020. [DOI: 10.1016/j.imu.2020.100309] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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17
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Alldred MJ, Chao HM, Lee SH, Beilin J, Powers BE, Petkova E, Strupp BJ, Ginsberg SD. Long-term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease. FASEB J 2019; 33:9871-9884. [PMID: 31180719 PMCID: PMC6704451 DOI: 10.1096/fj.201802669rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 05/07/2019] [Indexed: 01/12/2023]
Abstract
Choline is critical for normative function of 3 major pathways in the brain, including acetylcholine biosynthesis, being a key mediator of epigenetic regulation, and serving as the primary substrate for the phosphatidylethanolamine N-methyltransferase pathway. Sufficient intake of dietary choline is critical for proper brain function and neurodevelopment. This is especially important for brain development during the perinatal period. Current dietary recommendations for choline intake were undertaken without critical evaluation of maternal choline levels. As such, recommended levels may be insufficient for both mother and fetus. Herein, we examined the impact of perinatal maternal choline supplementation (MCS) in a mouse model of Down syndrome and Alzheimer's disease, the Ts65Dn mouse relative to normal disomic littermates, to examine the effects on gene expression within adult offspring at ∼6 and 11 mo of age. We found MCS produces significant changes in offspring gene expression levels that supersede age-related and genotypic gene expression changes. Alterations due to MCS impact every gene ontology category queried, including GABAergic neurotransmission, the endosomal-lysosomal pathway and autophagy, and neurotrophins, highlighting the importance of proper choline intake during the perinatal period, especially when the fetus is known to have a neurodevelopmental disorder such as trisomy.-Alldred, M. J., Chao, H. M., Lee, S. H., Beilin, J., Powers, B. E., Petkova, E., Strupp, B. J., Ginsberg, S. D. Long-term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.
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Affiliation(s)
- Melissa J. Alldred
- Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, USA
- Department of Psychiatry, (NYU) Langone Medical Center, New York, New York, USA
| | - Helen M. Chao
- Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, USA
- Department of Psychiatry, (NYU) Langone Medical Center, New York, New York, USA
| | - Sang Han Lee
- Center for Biomedical Imaging and Neuromodulation, Nathan Kline Institute, Orangeburg, New York, USA
- Department Neuroscience and Physiology, (NYU) Langone Medical Center, New York, New York, USA
| | - Judah Beilin
- Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, USA
| | - Brian E. Powers
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA
| | - Eva Petkova
- Child Psychiatry, Nathan Kline Institute, Orangeburg, New York, USA
- Department of Child and Adolescent Psychiatry, (NYU) Langone Medical Center, New York, New York, USA
| | - Barbara J. Strupp
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA
- Department of Psychology, Cornell University, Ithaca, New York, USA
| | - Stephen D. Ginsberg
- Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, USA
- Department of Psychiatry, (NYU) Langone Medical Center, New York, New York, USA
- Department Neuroscience and Physiology, (NYU) Langone Medical Center, New York, New York, USA
- New York University (NYU) Neuroscience Institute, NYU Langone Medical Center, New York, New York, USA
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18
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Fu X, Luo L, Yi R, Ding B, Wang C, Zhang W, Wang X, Yang Y, Chen C, Fei X, Hu D, Xu R. Transcriptome profiling in Eid1-KO mice brain shows that Eid1 links cell proliferation in the brain. Gene 2019; 717:143998. [PMID: 31381951 DOI: 10.1016/j.gene.2019.143998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 07/19/2019] [Accepted: 07/22/2019] [Indexed: 01/01/2023]
Abstract
Eid1 is a member of the EID protein family, which regulates differentiation, transcription and acetyltransferase activity. Accumulating evidence suggests that Eid1 is relevant to neurological disorder, but the main function of Eid1 is still unclear, especially in the brain. To better understand this issue, we generated Eid1-knockout (Eid1-KO) mice and profiled its gene expression changes in the brain by RNA sequencing. This study identified 2531 genes differentially expressed in Eid1-KO mice compared with the wild-type, then qRT-PCR verification demonstrated that the transcriptomic data are reliable. By protein-protein interaction cluster analysis, 'regulation of cell proliferation' were unexpectedly discovered as important Eid1 functions. We then isolated neural progenitor cells (NPCs) and showed that the number of neurospheres and the proliferation rate of Eid1-KO NPCs were obviously lower than that in the control group, furthermore, CCK-8 and immunofluorescence assay clearly demonstrated that the Eid1-KO NPCs showed significantly less cell proliferation than the control group. To the best of our knowledge, this is the first comprehensive report of the Eid1-KO transcriptome of mice brain. Our analysis and experimental data provide a foundation for further studies on understanding function of Eid1 in the brain.
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Affiliation(s)
- Xiaojun Fu
- Department of Neurosurgery, SanBo Brain Hospital, Capital Medical University, PR China
| | - Liang Luo
- Stem Cell Research Center, Seventh Medical Center of PLA General Hospital, Beijing, PR China; Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, PR China.
| | - Rui Yi
- Department of Health and Welfare, Seventh Medical Center, PLA General Hospital, PR China
| | - Boyun Ding
- Southern Medical University, Guangzhou, PR China
| | - Chongwu Wang
- Stem Cell Research Center, Seventh Medical Center of PLA General Hospital, Beijing, PR China
| | - Wei Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Xujie Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Yunshu Yang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Chen Chen
- Stem Cell Research Center, Seventh Medical Center of PLA General Hospital, Beijing, PR China
| | - Xiaowei Fei
- Stem Cell Research Center, Seventh Medical Center of PLA General Hospital, Beijing, PR China
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, PR China.
| | - Ruxiang Xu
- Stem Cell Research Center, Seventh Medical Center of PLA General Hospital, Beijing, PR China.
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19
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Meng J, Li Y, Zhang M, Li W, Zhou L, Wang Q, Lin L, Jiang L, Zhu W. A combination of curcumin, vorinostat and silibinin reverses A β-induced nerve cell toxicity via activation of AKT-MDM2-p53 pathway. PeerJ 2019; 7:e6716. [PMID: 31086728 PMCID: PMC6487801 DOI: 10.7717/peerj.6716] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 03/05/2019] [Indexed: 01/10/2023] Open
Abstract
Alzheimer’s disease (AD) is a significant health issue for the elderly and becoming increasingly common as the global population ages. Although many efforts have been made to elucidate its pathology, there is still a lack of effective clinical anti-AD agents. Previous research has shown the neuroprotective properties of a combination of curcumin and vorinostat. In this study, nine other neuroprotective agents were investigated to examine whether a three-drug combination of curcumin, vorinostat, and a new drug is more advantageous than the previous two-drug combination in alleviating amyloid beta (Aβ)-induced nerve cell toxicity. Cell viability assay was performed to screen these agents, and further validation tests, including determination of cellular oxidative stress, apoptosis, and activity of the AKT/MDM2/p53 pathway, were performed. Among the nine candidate compounds, only silibinin at 1 µM reduced Aβ25–35-induced toxicity in PC12 cells. The neuroprotective effects of 1 µM silibinin in combination with 5 µM curcumin and 0.5 µM vorinostat (CVS) was shown in PC12 cells, in which it decreased apoptosis and oxidative stress marker levels that were increased by 20 µM Aβ25–35. Western blotting results showed that CVS pretreatment significantly increased the phosphorylation of AKT, BAD, and MDM2, which resulted in decreased intracellular expression of p53. Further, immunofluorescence results showed reduced p53 levels in the nuclei of PC12 cells following CVS pretreatment, indicating a reduction in the p53-mediated transcriptional activity associated with Aβ25–35 exposure. In conclusion, our findings suggested that pretreatment with CVS protected PC12 cells from Aβ25–35-induced toxicity through modulation of the AKT/MDM2/p53 pathway. Thus, CVS may present a new therapeutic option for treating AD.
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Affiliation(s)
- Jia Meng
- Department of General Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yan Li
- Department of Pharmacy, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Mingming Zhang
- Department of General Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenjing Li
- Department of General Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lin Zhou
- Department of General Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qiujun Wang
- Department of General Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lin Lin
- Department of General Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lihong Jiang
- Department of General Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenliang Zhu
- Department of Pharmacy, Second Affiliated Hospital of Harbin Medical University, Harbin, China
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20
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Fu X, Ding B, Wang C, Chen C, Wang J, Fei X, Xu R. EID1 plays a crucial role in proliferation of neural stem cell. Biochem Biophys Res Commun 2019; 512:763-769. [PMID: 30926163 DOI: 10.1016/j.bbrc.2019.03.138] [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: 03/18/2019] [Accepted: 03/20/2019] [Indexed: 11/19/2022]
Abstract
EP300-interacting inhibitor of differentiation 1 (Eid1) regulates differentiation, transcription and acetyltransferase activity. But the main function of Eid1 in the brain is still unclear. To better understand this issue, we generated Eid1-knockout (Eid1-KO) mice. We found poorer learning and memory ability, and smaller volume of neonatal telencephalon in Eid1-KO group than wild-type (WT). Bioinformatics implied that Eid1 may directly regulate cell proliferation. We then isolated neural stem cells (NSCs) and discovered a slower proliferation rate in Eid1-KO NSCs. Moreover, based on bioinformatics results, we investigated the expression of phosphatidylinositol 3-kinase (PI3K)/AKT/GSK3β pathway by Western blotting assay, which showed attenuated in Eid1-KO group. Our data proved the first comprehensive report of Eid1 regulating NSCs proliferation via PI3K/AKT/GSK3β pathway, and provide a foundation for the role of EID1 in the brain.
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Affiliation(s)
- Xiaojun Fu
- Medical School of Chinese PLA & General Hospital of Chinese PLA, Beijing, PR China
| | - Boyun Ding
- Stem Cell Research Center, Neurosurgery Institute of PLA Army, Beijing, PR China
| | - Chongwu Wang
- Stem Cell Research Center, Neurosurgery Institute of PLA Army, Beijing, PR China
| | - Chen Chen
- Stem Cell Research Center, Neurosurgery Institute of PLA Army, Beijing, PR China
| | - Ji Wang
- Stem Cell Research Center, Neurosurgery Institute of PLA Army, Beijing, PR China
| | - Xiaowei Fei
- Stem Cell Research Center, Neurosurgery Institute of PLA Army, Beijing, PR China
| | - Ruxiang Xu
- Medical School of Chinese PLA & General Hospital of Chinese PLA, Beijing, PR China; Stem Cell Research Center, Neurosurgery Institute of PLA Army, Beijing, PR China.
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21
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Rahman MR, Islam T, Turanli B, Zaman T, Faruquee HM, Rahman MM, Mollah MNH, Nanda RK, Arga KY, Gov E, Moni MA. Network-based approach to identify molecular signatures and therapeutic agents in Alzheimer's disease. Comput Biol Chem 2018; 78:431-439. [PMID: 30606694 DOI: 10.1016/j.compbiolchem.2018.12.011] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 12/25/2018] [Indexed: 01/15/2023]
Abstract
Alzheimer's disease (AD) is a dynamic degeneration of the brain with progressive dementia. Considering the uncertainties in its molecular mechanism, in the present study, we employed network-based integrative analyses, and aimed to explore the key molecules and their associations with small drugs to identify potential biomarkers and therapeutic agents for the AD. First of all, we studied a transcriptome dataset and identified 1521 differentially expressed genes (DEGs). Integration of transcriptome data with protein-protein and transcriptional regulatory interactions resulted with central (hub) proteins (UBA52, RAC1, CREBBP, AR, RPS11, SMAD3, RPS6, RPL12, RPL15, and UBC), regulatory transcription factors (FOXC1, GATA2, YY1, FOXL1, NFIC, E2F1, USF2, SRF, PPARG, and JUN) and microRNAs (mir-335-5p, mir-26b-5p, mir-93-5p, mir-124-3p, mir-17-5p, mir-16-5p, mir-20a-5p, mir-92a-3p, mir-106b-5p, and mir-192-5p) as key signaling and regulatory molecules associated with transcriptional changes for the AD. Considering these key molecules as potential therapeutic targets and Connectivity Map (CMap) architecture, candidate small molecular agents (such as STOCK1N-35696) were identified as novel potential therapeutics for the AD. This study presents molecular signatures at RNA and protein levels which might be useful in increasing discernment of the molecular mechanisms, and potential drug targets and therapeutics to design effective treatment strategies for the AD.
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Affiliation(s)
- Md Rezanur Rahman
- Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia, Bangladesh; Department of Biochemistry and Biotechnology, School of Biomedical Science, Khwaja Yunus Ali University, Sirajgonj, Bangladesh
| | - Tania Islam
- Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia, Bangladesh
| | - Beste Turanli
- Department of Bioengineering, Istanbul Medeniyet University, Istanbul, Turkey; Department of Bioengineering, Marmara University, Istanbul, Turkey
| | - Toyfiquz Zaman
- Department of Biochemistry and Biotechnology, School of Biomedical Science, Khwaja Yunus Ali University, Sirajgonj, Bangladesh
| | - Hossain Md Faruquee
- Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia, Bangladesh; Translational Health, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Md Mafizur Rahman
- Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia, Bangladesh
| | - Md Nurul Haque Mollah
- Laboratory of Bioinformatics, Department of Statistics, University of Rajshahi, Rajshahi, Bangladesh
| | - Ranjan Kumar Nanda
- Translational Health, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | | | - Esra Gov
- Department of Bioengineering, Adana Science and Technology University, Adana, Turkey.
| | - Mohammad Ali Moni
- The University of Sydney, Sydney Medical School, School of Medical Sciences, Discipline of Biomedical Science, Sydney, New South Wales, Australia.
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22
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Chatterjee S, Cassel R, Schneider-Anthony A, Merienne K, Cosquer B, Tzeplaeff L, Halder Sinha S, Kumar M, Chaturbedy P, Eswaramoorthy M, Le Gras S, Keime C, Bousiges O, Dutar P, Petsophonsakul P, Rampon C, Cassel JC, Buée L, Blum D, Kundu TK, Boutillier AL. Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator. EMBO Mol Med 2018; 10:e8587. [PMID: 30275019 PMCID: PMC6220301 DOI: 10.15252/emmm.201708587] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 08/31/2018] [Accepted: 09/05/2018] [Indexed: 12/17/2022] Open
Abstract
Chromatin acetylation, a critical regulator of synaptic plasticity and memory processes, is thought to be altered in neurodegenerative diseases. Here, we demonstrate that spatial memory and plasticity (LTD, dendritic spine formation) deficits can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small-molecule activator of CBP/p300 histone acetyltransferases (HAT). At the transcriptional level, CSP-TTK21 re-established half of the hippocampal transcriptome in learning mice, likely through increased expression of neuronal activity genes and memory enhancers. At the epigenomic level, the hippocampus of tauopathic mice showed a significant decrease in H2B but not H3K27 acetylation levels, both marks co-localizing at TSS and CBP enhancers. Importantly, CSP-TTK21 treatment increased H2B acetylation levels at decreased peaks, CBP enhancers, and TSS, including genes associated with plasticity and neuronal functions, overall providing a 95% rescue of the H2B acetylome in tauopathic mice. This study is the first to provide in vivo proof-of-concept evidence that CBP/p300 HAT activation efficiently reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated with Alzheimer's disease lesions in mice.
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Affiliation(s)
- Snehajyoti Chatterjee
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
- LNCA, CNRS UMR 7364, Strasbourg, France
| | - Raphaelle Cassel
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
- LNCA, CNRS UMR 7364, Strasbourg, France
| | - Anne Schneider-Anthony
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
- LNCA, CNRS UMR 7364, Strasbourg, France
| | - Karine Merienne
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
- LNCA, CNRS UMR 7364, Strasbourg, France
| | - Brigitte Cosquer
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
- LNCA, CNRS UMR 7364, Strasbourg, France
| | - Laura Tzeplaeff
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
- LNCA, CNRS UMR 7364, Strasbourg, France
| | - Sarmistha Halder Sinha
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Manoj Kumar
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Piyush Chaturbedy
- Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Muthusamy Eswaramoorthy
- Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Stéphanie Le Gras
- CNRS, Inserm, UMR 7104, Microarray and Sequencing Platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France
| | - Céline Keime
- CNRS, Inserm, UMR 7104, Microarray and Sequencing Platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France
| | - Olivier Bousiges
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
- Laboratory of Biochemistry and Molecular Biology, Hôpital de Hautepierre, University Hospital of Strasbourg, Strasbourg, France
| | - Patrick Dutar
- Centre de Psychiatrie et Neurosciences, INSERM UMRS894, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Petnoi Petsophonsakul
- Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, CNRS, UPS, Université de Toulouse, Toulouse, France
| | - Claire Rampon
- Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, CNRS, UPS, Université de Toulouse, Toulouse, France
| | - Jean-Christophe Cassel
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
- LNCA, CNRS UMR 7364, Strasbourg, France
| | - Luc Buée
- Inserm, CHU-Lille, UMR-S 1172, Alzheimer & Tauopathies, Université de Lille, Lille, France
| | - David Blum
- Inserm, CHU-Lille, UMR-S 1172, Alzheimer & Tauopathies, Université de Lille, Lille, France
| | - Tapas K Kundu
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Anne-Laurence Boutillier
- Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
- LNCA, CNRS UMR 7364, Strasbourg, France
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23
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Chung CG, Lee H, Lee SB. Mechanisms of protein toxicity in neurodegenerative diseases. Cell Mol Life Sci 2018; 75:3159-3180. [PMID: 29947927 PMCID: PMC6063327 DOI: 10.1007/s00018-018-2854-4] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 06/06/2018] [Accepted: 06/07/2018] [Indexed: 12/12/2022]
Abstract
Protein toxicity can be defined as all the pathological changes that ensue from accumulation, mis-localization, and/or multimerization of disease-specific proteins. Most neurodegenerative diseases manifest protein toxicity as one of their key pathogenic mechanisms, the details of which remain unclear. By systematically deconstructing the nature of toxic proteins, we aim to elucidate and illuminate some of the key mechanisms of protein toxicity from which therapeutic insights may be drawn. In this review, we focus specifically on protein toxicity from the point of view of various cellular compartments such as the nucleus and the mitochondria. We also discuss the cell-to-cell propagation of toxic disease proteins that complicates the mechanistic understanding of the disease progression as well as the spatiotemporal point at which to therapeutically intervene. Finally, we discuss selective neuronal vulnerability, which still remains largely enigmatic.
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Affiliation(s)
- Chang Geon Chung
- Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, Republic of Korea
| | - Hyosang Lee
- Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, Republic of Korea.
| | - Sung Bae Lee
- Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, Republic of Korea.
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24
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Ziemka-Nalecz M, Jaworska J, Sypecka J, Zalewska T. Histone Deacetylase Inhibitors: A Therapeutic Key in Neurological Disorders? J Neuropathol Exp Neurol 2018; 77:855-870. [DOI: 10.1093/jnen/nly073] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Malgorzata Ziemka-Nalecz
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Joanna Jaworska
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Joanna Sypecka
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Teresa Zalewska
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
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25
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Liu H, Guo X, Han J, Luo R, Chen HF. Order-disorder transition of intrinsically disordered kinase inducible transactivation domain of CREB. J Chem Phys 2018; 148:225101. [PMID: 29907037 DOI: 10.1063/1.5027869] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Transcription factor cyclic Adenosine monophosphate response-element binding protein plays a critical role in the cyclic AMP response pathway via its intrinsically disordered kinase inducible transactivation domain (KID). KID is one of the most studied intrinsically disordered proteins (IDPs), although most previous studies focus on characterizing its disordered state structures. An interesting question that remains to be answered is how the order-disorder transition occurs at experimental conditions. Thanks to the newly developed IDP-specific force field ff14IDPSFF, the quality of conformer sampling for IDPs has been dramatically improved. In this study, molecular dynamics (MD) simulations were used to study the order-to-disorder transition kinetics of KID based on the good agreement with the experiment on its disordered-state properties. Specifically, we tested four force fields, ff99SBildn, ff99IDPs, ff14IDPSFF, and ff14IDPs in the simulations of KID and found that ff14IDPSFF can generate more diversified disordered conformers and also reproduce more accurate experimental secondary chemical shifts. Kinetics analysis of MD simulations demonstrates that the order-disorder transition of KID obeys the first-order kinetics, and the transition nucleus is I127/L128/L141. The possible transition pathways from the nucleus to the last folded residues were identified as I127-R125-L138-L141-S143-A145 and L128-R125-L138-L141-S143-A145 based on a residue-level dynamical network analysis. These computational studies not only provide testable prediction/hypothesis on the order-disorder transition of KID but also confirm that the ff14IDPSFF force field can be used to explore the correlation between the structure and function of IDPs.
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Affiliation(s)
- Hao Liu
- State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, SJTU-Yale Joint Center for Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Xiang Guo
- State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, SJTU-Yale Joint Center for Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Jingcheng Han
- State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, SJTU-Yale Joint Center for Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Ray Luo
- Departments of Molecular Biology and Biochemistry, Chemical Engineering and Materials Science, Biomedical Engineering, University of California, Irvine, California 92697-3900, USA
| | - Hai-Feng Chen
- State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, SJTU-Yale Joint Center for Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
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26
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Puigdellívol M, Saavedra A, Pérez-Navarro E. Cognitive dysfunction in Huntington's disease: mechanisms and therapeutic strategies beyond BDNF. Brain Pathol 2018; 26:752-771. [PMID: 27529673 DOI: 10.1111/bpa.12432] [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] [Received: 06/30/2016] [Accepted: 07/08/2016] [Indexed: 12/15/2022] Open
Abstract
One of the main focuses in Huntington's disease (HD) research, as well as in most neurodegenerative diseases, is the development of new therapeutic strategies, as currently there is no treatment to delay or prevent the progression of the disease. Neuronal dysfunction and neuronal death in HD are caused by a combination of interrelated pathogenic processes that lead to motor, cognitive and psychiatric symptoms. Understanding how mutant huntingtin impacts on a plethora of cellular functions could help to identify new molecular targets. Although HD has been classically classified as a neurodegenerative disease affecting voluntary movement, lately cognitive dysfunction is receiving increased attention as it is very invalidating for patients. Thus, an ambitious goal in HD research is to find altered molecular mechanisms that contribute to cognitive decline. In this review, we have focused on those findings related to corticostriatal and hippocampal cognitive dysfunction in HD, as well as on the underlying molecular mechanisms, which constitute potential therapeutic targets. These include alterations in synaptic plasticity, transcriptional machinery and neurotrophic and neurotransmitter signaling.
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Affiliation(s)
- Mar Puigdellívol
- Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.,Centro de Investigación Biomédica en Red (CIBER) sobre Enfermedades Neurodegenerativas (CIBERNED), Spain
| | - Ana Saavedra
- Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.,Centro de Investigación Biomédica en Red (CIBER) sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.,Institut de Neurociències, Universitat de Barcelona, Catalonia, Spain
| | - Esther Pérez-Navarro
- Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.,Centro de Investigación Biomédica en Red (CIBER) sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.,Institut de Neurociències, Universitat de Barcelona, Catalonia, Spain
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27
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Early Preclinical Changes in Hippocampal CREB-Binding Protein Expression in a Mouse Model of Familial Alzheimer’s Disease. Mol Neurobiol 2017; 55:4885-4895. [DOI: 10.1007/s12035-017-0690-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 07/12/2017] [Indexed: 12/22/2022]
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28
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Tran NQV, Nguyen AN, Takabe K, Yamagata Z, Miyake K. Pre-treatment with amitriptyline causes epigenetic up-regulation of neuroprotection-associated genes and has anti-apoptotic effects in mouse neuronal cells. Neurotoxicol Teratol 2017; 62:1-12. [PMID: 28511916 DOI: 10.1016/j.ntt.2017.05.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 05/09/2017] [Accepted: 05/11/2017] [Indexed: 12/12/2022]
Abstract
Antidepressants, such as imipramine and fluoxetine, are known to alter gene expression patterns by inducing changes in the epigenetic status of neuronal cells. There is also some evidence for the anti-apoptotic effect of various groups of antidepressants; however, this effect is complicated and cell-type dependent. Antidepressants of the tricyclic group, in particular amitriptyline, have been suggested to be beneficial in the treatment of neurodegenerative disorders. We examined whether amitriptyline exerts an anti-apoptotic effect via epigenetic mechanisms. Using DNA microarray, we analyzed global gene expression in mouse primary cultured neocortical neurons after treatment with amitriptyline and imipramine. The neuroprotection-associated genes, activating transcription factor 3 (Atf3) and heme oxygenase 1 (Hmox1), were up-regulated at both mRNA and protein levels by treatment with amitriptyline. Quantitative chromatin immunoprecipitation assay revealed that amitriptyline increased enrichments of trimethylation of histone H3 lysine 4 in the promoter regions of Atf3 and Hmox1 and acetylation of histone H3 lysine 9 in the promoter regions of Atf3, which indicate an active epigenetic status. Amitriptyline pre-treatment attenuated 1-methyl-4-phenylpyridinium ion (MPP+)- or amyloid β peptide 1-42 (Aβ1-42)-induced neuronal cell death and inhibited the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2). We found that Atf3 and Hmox1 were also up-regulated after Aβ1-42 treatment, and were further increased when pre-treated with amitriptyline. Interestingly, the highest up-regulation of Atf3 and Hmox1, at least at mRNA level, was observed after co-treatment with Aβ1-42 and amitriptyline, together with the loss of the neuroprotective effect. These findings suggest preconditioning and neuroprotective effects of amitriptyline; however, further investigations are needed for clarifying the contribution of epigenetic up-regulation of Atf3 and Hmox1 genes.
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Affiliation(s)
- Nguyen Quoc Vuong Tran
- Department of Health Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan
| | - An Nghia Nguyen
- Department of Health Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan
| | - Kyoko Takabe
- Department of Health Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan
| | - Zentaro Yamagata
- Department of Health Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan
| | - Kunio Miyake
- Department of Health Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan.
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29
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Vargas KG, Milic J, Zaciragic A, Wen KX, Jaspers L, Nano J, Dhana K, Bramer WM, Kraja B, van Beeck E, Ikram MA, Muka T, Franco OH. The functions of estrogen receptor beta in the female brain: A systematic review. Maturitas 2016; 93:41-57. [PMID: 27338976 DOI: 10.1016/j.maturitas.2016.05.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Accepted: 05/31/2016] [Indexed: 01/22/2023]
Abstract
Females have unique and additional risk factors for neurological disorders. Among classical estrogen receptors, estrogen receptor beta (ERβ) has been suggested as a therapeutic target. However, little is known about the role of ERβ in the female brain. Six electronic databases were searched for articles evaluating the role of ERβ in the female brain and the influence of age and menopause on ERβ function. After screening 3186 titles and abstracts, 49 articles were included in the review, all of which were animal studies. Of these, 19 focused on cellular signaling, 7 on neuroendocrine pathways, 8 on neurological disorders, 4 on neuroprotection and 19 on psychological and psychiatric outcomes (6 studies evaluated two or more outcomes). Our findings showed that ERβ phosphorylated and activated intracellular second messenger proteins and regulated protein expression of genes involved in neurological functions. It also promoted neurogenesis, modulated the neuroendocrine regulation of stress response, conferred neuroprotection against ischemia and inflammation, and reduced anxiety- and depression-like behaviors. Targeting ERβ may constitute a novel treatment for menopausal symptoms, including anxiety, depression, and neurological diseases. However, to establish potential therapeutic and preventive strategies targeting ERβ, future studies should be conducted in humans to further our understanding of the importance of ERβ in women's mental and cognitive health.
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Affiliation(s)
- Kris G Vargas
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Jelena Milic
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Asija Zaciragic
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Ke-Xin Wen
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Loes Jaspers
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Jana Nano
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Klodian Dhana
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | | | - Bledar Kraja
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands; Department of Biomedical Sciences, Faculty of Medicine, University of Medicine, Tirana, Albania; University Clinic of Gastrohepatology, University Hospital Center Mother Teresa, Tirana, Albania
| | - Ed van Beeck
- Department of Public Health, Erasmus University Medical Center, The Netherlands
| | - M Arfan Ikram
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands; Department of Neurology, Erasmus University Medical Center, The Netherlands; Department of Radiology, Erasmus University Medical Center, The Netherlands
| | - Taulant Muka
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
| | - Oscar H Franco
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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30
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Leng Y, Wang J, Wang Z, Liao HM, Wei M, Leeds P, Chuang DM. Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3. Int J Neuropsychopharmacol 2016; 19:pyw035. [PMID: 27207921 PMCID: PMC5006201 DOI: 10.1093/ijnp/pyw035] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 04/18/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Fibroblast growth factor 21, a novel regulator of glucose and lipid metabolism, has robust protective properties in neurons. However, its expression and function in glia are unknown. Valproic acid, a mood stabilizer and anticonvulsant, is a histone deacetylase inhibitor and a dynamic gene regulator. We investigated whether histone deacetylase inhibition by valproic acid and other inhibitors upregulates fibroblast growth factor 21 expression and, if so, sought to identify the histone deacetylase isoform(s) involved and their role in altering glial cell morphology. METHODS C6 glioma or primary cortical glial cultures were treated with histone deacetylase inhibitors, and fibroblast growth factor 21 levels and length of cell processes were subsequently measured. Histone deacetylase 1, 2, or 3 was also knocked down to detect which isoform was involved in regulating fibroblast growth factor 21 mRNA levels. Finally, knockdown and overexpression of fibroblast growth factor 21 were performed to determine whether it played a role in regulating cell process length. RESULTS Treatment of C6 cells or primary glial cultures with valproic acid elevated fibroblast growth factor 21 mRNA levels, extended cell process length, and markedly increased acetylated histone-H3 levels. Other histone deacetylase inhibitors including pan- and class I-specific inhibitors, or selective knockdown of histone deacetylase 2 or 3 isoform produced similar effects. Knockdown or overexpression of fibroblast growth factor 21 significantly decreased or increased C6 cell process length, respectively. CONCLUSIONS In glial cell line and primary glia, using pharmacological inhibition and selective gene silencing of histone deacetylases to boost fibroblast growth factor 21 mRNA levels results in elongation of cell processes. Our study provides a new mechanism via which histone deacetylase 2 and 3 participate in upregulating fibroblast growth factor 21 transcription and extending process outgrowth in glia.
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Affiliation(s)
- Yan Leng
- Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
| | | | | | | | | | | | - De-Maw Chuang
- Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
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31
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Zhong T, Ren F, Huang CS, Zou WY, Yang Y, Pan YD, Sun B, Wang E, Guo QL. Swimming exercise ameliorates neurocognitive impairment induced by neonatal exposure to isoflurane and enhances hippocampal histone acetylation in mice. Neuroscience 2015; 316:378-88. [PMID: 26748054 DOI: 10.1016/j.neuroscience.2015.12.049] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 12/25/2015] [Accepted: 12/28/2015] [Indexed: 12/21/2022]
Abstract
Isoflurane-induced neurocognitive impairment in the developing rodent brain is well documented, and regular physical exercise has been demonstrated to be a viable intervention for some types of neurocognitive impairment. This study was designed to investigate the potential protective effect of swimming exercise on both neurocognitive impairment caused by repeated neonatal exposure to isoflurane and the underlying molecular mechanism. Mice received 0.75% isoflurane exposures for 4h on postnatal days 7, 8, and 9. From the third month after anesthesia, the mice were subjected to regular swimming exercise for 4weeks, followed by a contextual fear condition (CFC) trial. We found that repeated neonatal exposure to isoflurane reduced freezing behavior during CFC testing and deregulated hippocampal histone H4K12 acetylation. Conversely, mice subjected to regular swimming exercise showed enhanced hippocampal H3K9, H4K5, and H4K12 acetylation levels, increased numbers of c-Fos-positive cells 1h after CFC training, and less isoflurane-induced memory impairment. We also observed increases in histone acetylation and of cAMP-response element-binding protein (CREB)-binding protein (CBP) during the swimming exercise program. The results suggest that neonatal isoflurane exposure-induced memory impairment was associated with dysregulation of H4K12 acetylation, which may lead to less hippocampal activation following learning tasks. Swimming exercise was associated with enhanced hippocampal histone acetylation and CBP expression. Exercise most likely ameliorated isoflurane-induced memory impairment by enhancing hippocampal histone acetylation and activating more neuron cells during memory formation.
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Affiliation(s)
- T Zhong
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China
| | - F Ren
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China
| | - C S Huang
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China
| | - W Y Zou
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China
| | - Y Yang
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China
| | - Y D Pan
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China
| | - B Sun
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China
| | - E Wang
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China
| | - Q L Guo
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China.
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32
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Increased acetyl and total histone levels in post-mortem Alzheimer's disease brain. Neurobiol Dis 2015; 74:281-94. [DOI: 10.1016/j.nbd.2014.11.023] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 11/20/2014] [Accepted: 11/26/2014] [Indexed: 11/19/2022] Open
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33
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Henry RA, Kuo YM, Bhattacharjee V, Yen TJ, Andrews AJ. Changing the selectivity of p300 by acetyl-CoA modulation of histone acetylation. ACS Chem Biol 2015; 10:146-56. [PMID: 25325435 DOI: 10.1021/cb500726b] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Determining how histone acetylation is regulated is vital for treating the many diseases associated with its misregulation, including heart disease, neurological disorders, and cancer. We have previously reported that acetyl-CoA levels alter p300 histone acetylation in a site-specific manner in vitro. Here, we further investigate how changing acetyl-CoA concentrations alter the histone acetylation pattern by altering p300 specificity. Interestingly, these changes are not a simple global change in acetylation, but rather site specific changes, whereby acetylation at some sites increase while others decrease. We also demonstrate how the p300 inhibitor C646 can pharmacologically alter p300 histone acetylation patterns in vitro and in cells. This study provides insight into the mechanisms regulating p300 residue specificity, a potential means for altering p300 dependent histone acetylation, and an investigation into altering histone acetylation patterns in cells.
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Affiliation(s)
- Ryan A. Henry
- Department of Cancer Biology, 333 Cottman Avenue, Fox Chase Cancer Center, Philadelphia, Pennsylvania United States
| | - Yin-Ming Kuo
- Department of Cancer Biology, 333 Cottman Avenue, Fox Chase Cancer Center, Philadelphia, Pennsylvania United States
| | - Vikram Bhattacharjee
- Department of Cancer Biology, 333 Cottman Avenue, Fox Chase Cancer Center, Philadelphia, Pennsylvania United States
| | - Timothy J. Yen
- Department of Cancer Biology, 333 Cottman Avenue, Fox Chase Cancer Center, Philadelphia, Pennsylvania United States
| | - Andrew J. Andrews
- Department of Cancer Biology, 333 Cottman Avenue, Fox Chase Cancer Center, Philadelphia, Pennsylvania United States
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Le JM, Squarize CH, Castilho RM. Histone modifications: Targeting head and neck cancer stem cells. World J Stem Cells 2014; 6:511-525. [PMID: 25426249 PMCID: PMC4178252 DOI: 10.4252/wjsc.v6.i5.511] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 09/10/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and is responsible for a quarter of a million deaths annually. The survival rate for HNSCC patients is poor, showing only minor improvement in the last three decades. Despite new surgical techniques and chemotherapy protocols, tumor resistance to chemotherapy remains a significant challenge for HNSCC patients. Numerous mechanisms underlie chemoresistance, including genetic and epigenetic alterations in cancer cells that may be acquired during treatment and activation of mitogenic signaling pathways, such as nuclear factor kappa-light-chain-enhancer-of activated B cell, that cause reduced apoptosis. In addition to dysfunctional molecular signaling, emerging evidence reveals involvement of cancer stem cells (CSCs) in tumor development and in tumor resistance to chemotherapy and radiotherapy. These observations have sparked interest in understanding the mechanisms involved in the control of CSC function and fate. Post-translational modifications of histones dynamically influence gene expression independent of alterations to the DNA sequence. Recent findings from our group have shown that pharmacological induction of post-translational modifications of tumor histones dynamically modulates CSC plasticity. These findings suggest that a better understanding of the biology of CSCs in response to epigenetic switches and pharmacological inhibitors of histone function may directly translate to the development of a mechanism-based strategy to disrupt CSCs. In this review, we present and discuss current knowledge on epigenetic modifications of HNSCC and CSC response to DNA methylation and histone modifications. In addition, we discuss chromatin modifications and their role in tumor resistance to therapy.
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Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways. Cell Death Dis 2014; 5:e1296. [PMID: 24946089 PMCID: PMC4611720 DOI: 10.1038/cddis.2014.247] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 04/22/2014] [Accepted: 04/23/2014] [Indexed: 12/13/2022]
Abstract
Acetylation homeostasis is thought to play a role in amyotrophic lateral sclerosis, and treatment with inhibitors of histone deacetylases has been considered a potential and attractive therapeutic approach, despite the lack of a thorough study of this class of proteins. In this study, we have considerably extended previous knowledge on the expression of 13 histone deacetylases in tissues (spinal cord and muscle) from mice carrying two different ALS-linked SOD1 mutations (G93A-SOD1 and G86R-SOD1). We have then focused on class III histone deacetylases SIRT1 and SIRT2 that are considered relevant in neurodegenerative diseases. SIRT1 decreases in the spinal cord, but increases in muscle during the progression of the disease, and a similar expression pattern is observed in the corresponding cell models (neuroblastoma and myoblasts). SIRT2 mRNA expression increases in the spinal cord in both G93A-SOD1 and G86R-SOD1 mice but protein expression is substantially unchanged in all the models examined. At variance with other sirtuin modulators (sirtinol, AGK2 and SRT1720), the well-known SIRT1 inhibitor Ex527 has positive effects on survival of neuronal cells expressing mutant SOD1, but this effect is neither mediated by SIRT1 inhibition nor by SIRT2 inhibition. These data call for caution in proposing sirtuin modulation as a target for treatment.
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Yildirim F, Ji S, Kronenberg G, Barco A, Olivares R, Benito E, Dirnagl U, Gertz K, Endres M, Harms C, Meisel A. Histone acetylation and CREB binding protein are required for neuronal resistance against ischemic injury. PLoS One 2014; 9:e95465. [PMID: 24748101 PMCID: PMC3991684 DOI: 10.1371/journal.pone.0095465] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Accepted: 03/26/2014] [Indexed: 11/19/2022] Open
Abstract
Epigenetic transcriptional regulation by histone acetylation depends on the balance between histone acetyltransferase (HAT) and deacetylase activities (HDAC). Inhibition of HDAC activity provides neuroprotection, indicating that the outcome of cerebral ischemia depends crucially on the acetylation status of histones. In the present study, we characterized the changes in histone acetylation levels in ischemia models of focal cerebral ischemia and identified cAMP-response element binding protein (CREB)–binding protein (CBP) as a crucial factor in the susceptibility of neurons to ischemic stress. Both neuron-specific RNA interference and neurons derived from CBP heterozygous knockout mice showed increased damage after oxygen-glucose deprivation (OGD) in vitro. Furthermore, we demonstrated that ischemic preconditioning by a short (5 min) subthreshold occlusion of the middle cerebral artery (MCA), followed 24 h afterwards by a 30 min occlusion of the MCA, increased histone acetylation levels in vivo. Ischemic preconditioning enhanced CBP recruitment and histone acetylation at the promoter of the neuroprotective gene gelsolin leading to increased gelsolin expression in neurons. Inhibition of CBP's HAT activity attenuated neuronal ischemic preconditioning. Taken together, our findings suggest that the levels of CBP and histone acetylation determine stroke outcome and are crucially associated with the induction of an ischemia-resistant state in neurons.
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Affiliation(s)
- Ferah Yildirim
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Shengbo Ji
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Golo Kronenberg
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Klinik und Poliklinik für Psychiatrie, Campus Mitte, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Angel Barco
- Instituto de Neurociencias de Alicante (Universidad Miguel Hernandez-Consejo Superior de Investigaciones Cientificas), Campus de Sant Joan, Sant Joan d'Alacant, Alicante, Spain
| | - Roman Olivares
- Instituto de Neurociencias de Alicante (Universidad Miguel Hernandez-Consejo Superior de Investigaciones Cientificas), Campus de Sant Joan, Sant Joan d'Alacant, Alicante, Spain
| | - Eva Benito
- Instituto de Neurociencias de Alicante (Universidad Miguel Hernandez-Consejo Superior de Investigaciones Cientificas), Campus de Sant Joan, Sant Joan d'Alacant, Alicante, Spain
| | - Ulrich Dirnagl
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité–Universitätsmedizin Berlin, Berlin, Germany
- ExcellenceCluster NeuroCure, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Karen Gertz
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité–Universitätsmedizin Berlin, Berlin, Germany
- ExcellenceCluster NeuroCure, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Matthias Endres
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité–Universitätsmedizin Berlin, Berlin, Germany
- ExcellenceCluster NeuroCure, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Christoph Harms
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité–Universitätsmedizin Berlin, Berlin, Germany
- * E-mail:
| | - Andreas Meisel
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité–Universitätsmedizin Berlin, Berlin, Germany
- ExcellenceCluster NeuroCure, Charité–Universitätsmedizin Berlin, Berlin, Germany
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Meng J, Li Y, Camarillo C, Yao Y, Zhang Y, Xu C, Jiang L. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity. PLoS One 2014; 9:e85570. [PMID: 24409332 PMCID: PMC3883700 DOI: 10.1371/journal.pone.0085570] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Accepted: 11/30/2013] [Indexed: 12/31/2022] Open
Abstract
With the trend of an increasing aged population worldwide, Alzheimer's disease (AD), an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC) inhibitor, suberoylanilidehydroxamic acid (SAHA), may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25–35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.
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Affiliation(s)
- Jia Meng
- Department of Geriatrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yan Li
- Department of Pharmacy, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Cynthia Camarillo
- The Center of Excellence in Neuroscience, Texas Tech University Health Sciences Center, El Paso, Texas, United States of America
| | - Yue Yao
- Department of Geriatrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yina Zhang
- Department of Geriatrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- * E-mail: (YZ); (LJ)
| | - Chun Xu
- The Center of Excellence in Neuroscience, Texas Tech University Health Sciences Center, El Paso, Texas, United States of America
| | - Lihong Jiang
- Department of Geriatrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- * E-mail: (YZ); (LJ)
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Chen JF. Adenosine receptor control of cognition in normal and disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2014; 119:257-307. [PMID: 25175970 DOI: 10.1016/b978-0-12-801022-8.00012-x] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Adenosine and adenosine receptors (ARs) are increasingly recognized as important therapeutic targets for controlling cognition under normal and disease conditions for its dual roles of neuromodulation as well as of homeostatic function in the brain. This chapter first presents the unique ability of adenosine, by acting on the inhibitory A1 and facilitating A2A receptor, to integrate dopamine, glutamate, and BNDF signaling and to modulate synaptic plasticity (e.g., long-term potentiation and long-term depression) in brain regions relevant to learning and memory, providing the molecular and cellular bases for adenosine receptor (AR) control of cognition. This led to the demonstration of AR modulation of social recognition memory, working memory, reference memory, reversal learning, goal-directed behavior/habit formation, Pavlovian fear conditioning, and effort-related behavior. Furthermore, human and animal studies support that AR activity can also, through cognitive enhancement and neuroprotection, reverse cognitive impairments in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, and schizophrenia. Lastly, epidemiological evidence indicates that regular human consumption of caffeine, the most widely used psychoactive drug and nonselective AR antagonists, is associated with the reduced cognitive decline in aging and AD patients, and with the reduced risk in developing PD. Thus, there is a convergence of the molecular studies revealing AR as molecular targets for integrating neurotransmitter signaling and controlling synaptic plasticity, with animal studies demonstrating the strong procognitive impact upon AR antagonism in normal and disease brains and with epidemiological and clinical evidences in support of caffeine and AR drugs for therapeutic modulation of cognition. Since some of adenosine A2A receptor antagonists are already in phase III clinical trials for motor benefits in PD patients with remarkable safety profiles, additional animal and human studies to better understand the mechanism underlying the AR-mediated control of cognition under normal and disease conditions will provide the required rationale to stimulate the necessary clinical investigation to rapidly translate adenosine and AR drug as a novel strategy to control memory impairment in neuropsychiatric disorders.
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Affiliation(s)
- Jiang-Fan Chen
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA; The Molecular Medicine Institute, Wenzhou Medical University, Wenzhou, Zhejiang, PR China.
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Brochier C, Langley B. Chromatin modifications associated with DNA double-strand breaks repair as potential targets for neurological diseases. Neurotherapeutics 2013; 10:817-30. [PMID: 24072514 PMCID: PMC3805873 DOI: 10.1007/s13311-013-0210-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The integrity of the genome is continuously challenged by both endogenous and exogenous DNA damaging agents. Neurons, due to their post-mitotic state, high metabolism, and longevity are particularly prone to the accumulation of DNA lesions. Indeed, DNA damage has been suggested as a major contributor to both age-associated neurodegenerative diseases and acute neurological injury. The DNA damage response is a key factor in maintaining genome integrity. It relies on highly dynamic posttranslational modifications of the chromatin and DNA repair proteins to allow signaling, access, and repair of the lesion. Drugs that modulate the activity of the enzymes responsible for these modifications have emerged as attractive therapeutic compounds to treat neurodegeneration. In this review, we discuss the role of DNA double-strand breaks and abnormal chromatin modification patterns in a range of neurodegenerative conditions, and the chromatin modifiers that might ameliorate them. Finally, we suggest that understanding the epigenetic modifications specific to neuronal DNA repair is crucial for the development of efficient neurotherapeutic strategies.
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Affiliation(s)
- Camille Brochier
- The Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY, 10605, USA,
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Schneider A, Chatterjee S, Bousiges O, Selvi BR, Swaminathan A, Cassel R, Blanc F, Kundu TK, Boutillier AL. Acetyltransferases (HATs) as targets for neurological therapeutics. Neurotherapeutics 2013; 10:568-88. [PMID: 24006237 PMCID: PMC3805875 DOI: 10.1007/s13311-013-0204-7] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen long-term events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.
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Affiliation(s)
- Anne Schneider
- />Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS, GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
| | - Snehajyoti Chatterjee
- />Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS, GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
| | - Olivier Bousiges
- />Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS, GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
| | - B. Ruthrotha Selvi
- />Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064 India
| | - Amrutha Swaminathan
- />Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064 India
| | - Raphaelle Cassel
- />Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS, GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
| | - Frédéric Blanc
- />Service de Neuropsychologie and CMRR (Centre Mémoire de Ressources et de recherche) Laboratoire ICube, Université de Strasbourg, CNRS, équipe IMIS-Neurocrypto, 1, place de l’Hôpital, 67000 Strasbourg, France
| | - Tapas K. Kundu
- />Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064 India
| | - Anne-Laurence Boutillier
- />Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS, GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
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Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons. J Neurosci 2013; 33:8621-32. [PMID: 23678107 DOI: 10.1523/jneurosci.5214-12.2013] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Histone deacetylase (HDAC) inhibitors have been used to promote neuronal survival and ameliorate neurological dysfunction in a host of neurodegenerative disease models. The precise molecular mechanisms whereby HDAC inhibitors prevent neuronal death are currently the focus of intensive research. Here we demonstrate that HDAC inhibition prevents DNA damage-induced neurodegeneration by modifying the acetylation pattern of the tumor suppressor p53, which decreases its DNA-binding and transcriptional activation of target genes. Specifically, we identify that acetylation at K382 and K381 prevents p53 from associating with the pro-apoptotic PUMA gene promoter, activating transcription, and inducing apoptosis in mouse primary cortical neurons. Paradoxically, acetylation of p53 at the same lysines in various cancer cell lines leads to the induction of PUMA expression and death. Together, our data provide a molecular understanding of the specific outcomes of HDAC inhibition and suggest that strategies aimed at enhancing p53 acetylation at K381 and K382 might be therapeutically viable for capturing the beneficial effects in the CNS, without compromising tumor suppression.
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Increasing Tip60 HAT levels rescues axonal transport defects and associated behavioral phenotypes in a Drosophila Alzheimer's disease model. J Neurosci 2013; 33:7535-47. [PMID: 23616558 DOI: 10.1523/jneurosci.3739-12.2013] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Axonal transport defects and axonopathy are prominent in early preclinical stages of Alzheimer's disease (AD), often preceding known disease-related pathology by over a year. As epigenetic transcriptional regulatory mechanisms, such as histone acetylation, are critical for neurogenesis, it is postulated that their misregulation might be linked to early pathophysiological mechanisms that contribute to AD. The histone acetyltransferase (HAT) Tip60 epigenetically regulates genes enriched for neuronal functions and is implicated in AD via its formation of a transcriptional regulatory complex with the amyloid precursor protein (APP) intracellular domain. Disruption of APP function is associated with axonal transport defects, raising the possibility that an epigenetic role for Tip60 might also be involved. Here, we examine whether Tip60 HAT activity functions in axonal transport using Drosophila CNS motor neurons as a well-characterized transport model. We show that reduction of Tip60 HAT activity in the nervous system causes axonopathy and transport defects associated with epigenetic misregulation of certain axonal transport-linked Tip60 target genes. Functional consequences of these defects are evidenced by reduced locomotion activity of the mutant Tip60 larvae, and these phenotypes can be partially rescued with certain histone deacetylase inhibitors. Finally, we demonstrate that Tip60 function in axonal transport is mediated by APP and that, remarkably, excess Tip60 exerts a neuroprotective role in APP-induced axonal transport and functional locomotion defects. Our observations highlight a novel functional interactive role between Tip60 HAT activity and APP in axonal transport and provide insight into the importance of specific HAT modulators for cognitive disorder treatment.
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Liu RY, Zhang Y, Baxter DA, Smolen P, Cleary LJ, Byrne JH. Deficit in long-term synaptic plasticity is rescued by a computationally predicted stimulus protocol. J Neurosci 2013; 33:6944-9. [PMID: 23595752 PMCID: PMC3690371 DOI: 10.1523/jneurosci.0643-13.2013] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 03/13/2013] [Accepted: 03/15/2013] [Indexed: 01/01/2023] Open
Abstract
Mutations in the gene encoding CREB-binding protein (CBP) cause deficits in long-term plasticity, learning, and memory. Here, long-term synaptic facilitation (LTF) at Aplysia sensorimotor synapses in cell culture was used as a model system to investigate methods for overcoming deficits in LTF produced by a CBP knockdown. Injecting CBP-siRNA into individual sensory neurons reduced CBP levels and impaired LTF produced by a standard protocol of five 5-min pulses of serotonin (5-HT) delivered at 20 min interstimulus intervals. A computational model, which simulated molecular processes underlying LTF induction, predicted a rescue protocol of five pulses of 5-HT at non-uniform interstimulus intervals that overcame the consequences of reduced CBP and restored LTF. These results suggest that complementary empirical and computational studies can identify methods for ameliorating impairments of learning attributable to molecular lesions.
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Affiliation(s)
- Rong-Yu Liu
- Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas 77030
| | - Yili Zhang
- Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas 77030
| | - Douglas A. Baxter
- Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas 77030
| | - Paul Smolen
- Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas 77030
| | - Leonard J. Cleary
- Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas 77030
| | - John H. Byrne
- Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas 77030
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Lovatel GA, Elsner VR, Bertoldi K, Vanzella C, Moysés FDS, Vizuete A, Spindler C, Cechinel LR, Netto CA, Muotri AR, Siqueira IR. Treadmill exercise induces age-related changes in aversive memory, neuroinflammatory and epigenetic processes in the rat hippocampus. Neurobiol Learn Mem 2013; 101:94-102. [PMID: 23357282 DOI: 10.1016/j.nlm.2013.01.007] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 01/11/2013] [Accepted: 01/20/2013] [Indexed: 01/30/2023]
Abstract
It has been described that exercise can modulate both inflammatory response and epigenetic modifications, although the effect of exercise on these parameters during the normal brain aging process yet remains poorly understood. Here, we investigated the effect of aging and treadmill exercise on inflammatory and epigenetic parameters specifically pro and anti-inflammatory cytokines levels, activation of NF-kB and histone H4 acetylation levels in hippocampus from Wistar rats. Additionally, we evaluated aversive memory through inhibitory avoidance task. Rats of 3 and 20 months of age were assigned to non-exercised (sedentary) and exercised (running daily for 20 min for 2 weeks) groups. The effect of daily forced exercise in the treadmill was assessed. The levels of inflammatory and epigenetic parameters were determined 1h, 18 h, 3 days or 7 days after the last training session of exercise. It was observed an age-related decline on aversive memory, as well as aged rats showed increased hippocampal levels of inflammatory markers, such as TNFα, IL1-β and NF-kB and decreased IL-4 levels, an anti-inflammatory cytokine. Moreover, lower levels of global histone H4 acetylation were also observed in hippocampi from aged rats. Interestingly, there was a significant correlation between the biochemical markers and the inhibitory avoidance test performance. The forced exercise protocol ameliorated aging-related memory decline, decreased pro-inflammatory markers and increased histone H4 acetylation levels in hippocampi 20-months-old rats, while increased acutely IL-4 levels in hippocampi from young adult rats. Together, these results suggest that an imbalance of inflammatory markers might be involved to the aging-related aversive memory impairment. Additionally, our exercise protocol may reverse aging-related memory decline through improving cytokine profile.
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Affiliation(s)
- Gisele Agustini Lovatel
- Programa de Pós-Graduação em Ciências Biológicas: Neurociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Brennan P, Filippakopoulos P, Knapp S. The therapeutic potential of acetyl-lysine and methyl-lysine effector domains. ACTA ACUST UNITED AC 2012. [DOI: 10.1016/j.ddstr.2012.04.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Pirooznia SK, Sarthi J, Johnson AA, Toth MS, Chiu K, Koduri S, Elefant F. Tip60 HAT activity mediates APP induced lethality and apoptotic cell death in the CNS of a Drosophila Alzheimer's disease model. PLoS One 2012; 7:e41776. [PMID: 22848598 PMCID: PMC3406101 DOI: 10.1371/journal.pone.0041776] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Accepted: 06/29/2012] [Indexed: 12/26/2022] Open
Abstract
Histone acetylation of chromatin promotes dynamic transcriptional responses in neurons that influence neuroplasticity critical for cognitive ability. It has been demonstrated that Tip60 histone acetyltransferase (HAT) activity is involved in the transcriptional regulation of genes enriched for neuronal function as well as the control of synaptic plasticity. Accordingly, Tip60 has been implicated in the neurodegenerative disorder Alzheimer's disease (AD) via transcriptional regulatory complex formation with the AD linked amyloid precursor protein (APP) intracellular domain (AICD). As such, inappropriate complex formation may contribute to AD-linked neurodegeneration by misregulation of target genes involved in neurogenesis; however, a direct and causative epigenetic based role for Tip60 HAT activity in this process during neuronal development in vivo remains unclear. Here, we demonstrate that nervous system specific loss of Tip60 HAT activity enhances APP mediated lethality and neuronal apoptotic cell death in the central nervous system (CNS) of a transgenic AD fly model while remarkably, overexpression of Tip60 diminishes these defects. Notably, all of these effects are dependent upon the C-terminus of APP that is required for transcriptional regulatory complex formation with Tip60. Importantly, we show that the expression of certain AD linked Tip60 gene targets critical for regulating apoptotic pathways are modified in the presence of APP. Our results are the first to demonstrate a functional interaction between Tip60 and APP in mediating nervous system development and apoptotic neuronal cell death in the CNS of an AD fly model in vivo, and support a novel neuroprotective role for Tip60 HAT activity in AD neurodegenerative pathology.
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Affiliation(s)
| | | | | | | | | | | | - Felice Elefant
- Department of Biology, Drexel University, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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Hosseini SMR, Tajdini M, Modabbernia A, Akhondzadeh S. Fluoxetine for multiple sclerosis. Hippokratia 2012. [DOI: 10.1002/14651858.cd009866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Seyed Mohammad Reza Hosseini
- Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences; Department of Psychiatry; South Kargar Street Tehran Iran 13337
| | - Masih Tajdini
- Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences; Department of Psychiatry; South Kargar Street Tehran Iran 13337
| | - Amirhossein Modabbernia
- Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences; Department of Psychiatry; South Kargar Street Tehran Iran 13337
| | - Shahin Akhondzadeh
- Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences; Department of Psychiatry; South Kargar Street Tehran Iran 13337
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Lagali PS, Picketts DJ. Matters of life and death: the role of chromatin remodeling proteins in retinal neuron survival. J Ocul Biol Dis Infor 2012; 4:111-20. [PMID: 23289056 PMCID: PMC3382293 DOI: 10.1007/s12177-012-9080-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Accepted: 03/05/2012] [Indexed: 12/13/2022] Open
Abstract
Retinal neurons are highly vulnerable to a diverse array of neurotoxic stimuli that leads to their degeneration, which is a major contributor to blindness. This review summarizes the role of epigenetic factors in mediating neuronal homeostasis and survival to protect against cell death and neurodegenerative conditions. Studies in human patients and mouse models implicate numerous chromatin modifications in neuroprotective processes including histone protein acetylation and methylation, DNA methylation, and ATP-dependent nucleosome remodeling. Recent research has begun to uncover specific epigenetic mechanisms invoked by neurotoxic stimuli. Continued investigation in this area will be the key to the generation of therapeutic strategies for the intervention of retinal neurodegenerative diseases.
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Affiliation(s)
- Pamela S Lagali
- Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON Canada K1H 8L6 ; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON Canada K1H 8M5
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Graham RK, Ehrnhoefer DE, Hayden MR. Caspase-6 and neurodegeneration. Trends Neurosci 2011; 34:646-56. [DOI: 10.1016/j.tins.2011.09.001] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 09/02/2011] [Accepted: 09/13/2011] [Indexed: 01/10/2023]
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Giralt A, Puigdellívol M, Carretón O, Paoletti P, Valero J, Parra-Damas A, Saura CA, Alberch J, Ginés S. Long-term memory deficits in Huntington's disease are associated with reduced CBP histone acetylase activity. Hum Mol Genet 2011; 21:1203-16. [PMID: 22116937 DOI: 10.1093/hmg/ddr552] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by an expanded CAG/polyglutamine repeat in the coding region of the huntingtin (htt) gene. Although HD is classically considered a motor disorder, there is now considerable evidence that early cognitive deficits appear in patients before the onset of motor disturbances. Here we demonstrate early impairment of long-term spatial and recognition memory in heterozygous HD knock-in mutant mice (Hdh(Q7/Q111)), a genetically accurate HD mouse model. Cognitive deficits are associated with reduced hippocampal expression of CREB-binding protein (CBP) and diminished levels of histone H3 acetylation. In agreement with reduced CBP, the expression of CREB/CBP target genes related to memory, such c-fos, Arc and Nr4a2, was significantly reduced in the hippocampus of Hdh(Q7/Q111) mice compared with wild-type mice. Finally, and consistent with a role of CBP in cognitive impairment in Hdh(Q7/Q111) mice, administration of the histone deacetylase inhibitor trichostatin A rescues recognition memory deficits and transcription of selective CREB/CBP target genes in Hdh(Q7/Q111) mice. These findings demonstrate an important role for CBP in cognitive dysfunction in HD and suggest the use of histone deacetylase inhibitors as a novel therapeutic strategy for the treatment of memory deficits in this disease.
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Affiliation(s)
- A Giralt
- Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
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