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Di Tella S, Zinzi P, Anzuino I, Lo Monaco MR, Tondinelli A, Magistri M, Petracca M, Solito M, Calabresi P, Bentivoglio AR, Silveri MC. Social cognition in basal ganglia pathologies: Theory of Mind in Huntington's and Parkinson's diseases. Soc Cogn Affect Neurosci 2025; 20:nsaf007. [PMID: 39948742 PMCID: PMC11840954 DOI: 10.1093/scan/nsaf007] [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: 04/26/2024] [Revised: 12/20/2024] [Accepted: 02/10/2025] [Indexed: 02/21/2025] Open
Abstract
Theory of Mind (ToM) is the ability to predict the behaviour of others by inferring their cognitive and affective states. The literature suggests that different neural substrates within the basal ganglia are involved in the affective (ventral striatum) and cognitive (dorsal striatum) components of ToM. We investigated ToM dysfunction in two different basal ganglia pathologies, Huntington's disease (HD) and Parkinson's disease (PD), in their early stages. Indeed, a different progression of neurodegeneration from the dorsal striatum to the ventral striatum is described in the two diseases. We also investigated whether there is a correlation between ToM and executive function. Twenty-one patients with HD, 21 with PD, and 22 healthy subjects (HS) were recruited. All participants completed a ToM assessment using the Yoni task, which assesses both cognitive and affective components at two levels of meta-representational difficulty (i.e. first-order items only require inferring the mental state of a person, while second-order items also require inferring the mental states of a person about others). The clinical groups also underwent a full neuropsychological assessment. In HD patients, both cognitive and affective ToM were equally impaired, whereas in PD patients, impairment of the cognitive component predominated. Specifically, compared to HS, HD patients scored lower on both inferential levels and on both cognitive and affective components, whereas PD patients scored lower than HS only on second-order and cognitive items. In the clinical groups, there was an imbalance between the cognitive and affective components, with higher accuracy on affective items. Performance on the Yoni task did not correlate with tests assessing executive functions. We suggest that the different pattern of ToM alteration in HD and PD may be a result of differential involvement of the ventral and dorsal striatum and that ToM abilities in these clinical populations are not directly supported by executive functioning.
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Affiliation(s)
- Sonia Di Tella
- Università Cattolica del Sacro Cuore, Department of Psychology, Milan 20123, Italy
| | - Paola Zinzi
- Movement Disorders Unit, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, Rome 00168, Italy
- Clinical Psychology Unit, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, Rome 00168, Italy
| | - Isabella Anzuino
- Università Cattolica del Sacro Cuore, Department of Psychology, Milan 20123, Italy
| | - Maria Rita Lo Monaco
- Center for the Medicine of Aging, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, Rome 00168, Italy
- Università Cattolica del Sacro Cuore, Institute of Internal Medicine and Geriatrics, Rome 00168, Italy
| | - Alice Tondinelli
- Università Cattolica del Sacro Cuore, Department of Psychology, Milan 20123, Italy
| | - Marianna Magistri
- Università Cattolica del Sacro Cuore, Department of Psychology, Milan 20123, Italy
| | - Martina Petracca
- Movement Disorders Unit, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, Rome 00168, Italy
| | - Marcella Solito
- Movement Disorders Unit, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, Rome 00168, Italy
- Università Cattolica del Sacro Cuore, Institute of Neurology, Rome 00168, Italy
| | - Paolo Calabresi
- Movement Disorders Unit, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, Rome 00168, Italy
- Università Cattolica del Sacro Cuore, Institute of Neurology, Rome 00168, Italy
| | - Anna Rita Bentivoglio
- Movement Disorders Unit, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, Rome 00168, Italy
- Università Cattolica del Sacro Cuore, Institute of Neurology, Rome 00168, Italy
| | - Maria Caterina Silveri
- Università Cattolica del Sacro Cuore, Department of Psychology, Milan 20123, Italy
- Center for the Medicine of Aging, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, Rome 00168, Italy
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Solem MA, Pelzel RG, Rozema NB, Brown TG, Reid E, Mansky RH, Gomez-Pastor R. Absence of hippocampal pathology persists in the Q175DN mouse model of Huntington's disease despite elevated HTT aggregation. J Huntingtons Dis 2025; 14:59-84. [PMID: 39973391 PMCID: PMC11974504 DOI: 10.1177/18796397251316762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
BackgroundHuntington's disease (HD) is a neurodegenerative disorder causing motor, cognitive, and psychiatric impairments, with the striatum being the most affected brain region. However, the role of other regions, such as the hippocampus, in HD remains less understood.ObjectiveHere, we study the comparative impact of enhanced mHTT aggregation and neuropathology in the striatum and hippocampus of two HD mouse models.MethodsWe utilized the zQ175 as a control HD mouse model and the Q175DN mice lacking the PGK-Neomycin cassette generated in house. We performed a comparative characterization of the neuropathology between zQ175 and Q175DN mice in the striatum and the hippocampus by assessing HTT aggregation, neuronal and glial pathology, chaperone expression, and synaptic density.ResultsWe showed that Q175DN mice presented enhanced mHTT aggregation in both striatum and hippocampus compared to zQ175. Striatal neurons showed a greater susceptibility to enhanced accumulation of mHTT in Q175DN. On the contrary, no signs of hippocampal pathology were found in zQ175 and absence of hippocampal pathology persisted in Q175DN mice despite higher levels of mHTT. In addition, Q175DN hippocampus presented increased synaptic density, decreased Iba1+ microglia density and enhanced HSF1 levels in specific subregions of the hippocampus compared to zQ175.ConclusionsQ175DN mice are a valuable tool to understand the fundamental susceptibility differences to mHTT toxicity between striatal neurons and other neuronal subtypes. Furthermore, our findings also suggest that cognitive deficits observed in HD animals might arise from either striatum dysfunction or other regions involved in cognitive processes but not from hippocampal degeneration.
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Affiliation(s)
- Melissa A Solem
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Ross G Pelzel
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Nicholas B Rozema
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Taylor G Brown
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Emma Reid
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Rachel H Mansky
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Rocio Gomez-Pastor
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA
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Xu Z, He S, Begum MM, Han X. Myelin Lipid Alterations in Neurodegenerative Diseases: Landscape and Pathogenic Implications. Antioxid Redox Signal 2024; 41:1073-1099. [PMID: 39575748 PMCID: PMC11971557 DOI: 10.1089/ars.2024.0676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 12/14/2024]
Abstract
Significance: Lipids, which constitute the highest portion (over 50%) of brain dry mass, are crucial for brain integrity, energy homeostasis, and signaling regulation. Emerging evidence revealed that lipid profile alterations and abnormal lipid metabolism occur during normal aging and in different forms of neurodegenerative diseases. Moreover, increasing genome-wide association studies have validated new targets on lipid-associated pathways involved in disease development. Myelin, the protective sheath surrounding axons, is crucial for efficient neural signaling transduction. As the primary site enriched with lipids, impairments of myelin are increasingly recognized as playing significant and complex roles in various neurodegenerative diseases, beyond simply being secondary effects of neuronal loss. Recent Advances: With advances in the lipidomics field, myelin lipid alterations and their roles in contributing to or reflecting the progression of diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others, have recently caught great attention. Critical Issues: This review summarizes recent findings of myelin lipid alterations in the five most common neurodegenerative diseases and discusses their implications in disease pathogenesis. Future Directions: By highlighting myelin lipid abnormalities in neurodegenerative diseases, this review aims to encourage further research focused on lipids and the development of new lipid-oriented therapeutic approaches in this area. Antioxid. Redox Signal. 00, 000-000.
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Affiliation(s)
- Ziying Xu
- Sam and Ann Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, Texas, USA
| | - Sijia He
- Sam and Ann Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, Texas, USA
| | - Mst Marium Begum
- Sam and Ann Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, Texas, USA
| | - Xianlin Han
- Sam and Ann Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, Texas, USA
- Department of Medicine, UT Health San Antonio, San Antonio, Texas, USA
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Solem MA, Pelzel R, Rozema NB, Brown TG, Reid E, Mansky RH, Gomez-Pastor R. Enhanced Hippocampal Spare Capacity in Q175DN Mice Despite Elevated mHTT Aggregation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.14.618355. [PMID: 39464002 PMCID: PMC11507687 DOI: 10.1101/2024.10.14.618355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Background Huntington's disease (HD) is a neurodegenerative disease resulting in devastating motor, cognitive, and psychiatric deficits. The striatum is a brain region that controls movement and some forms of cognition and is most significantly impacted in HD. However, despite well-documented deficits in learning and memory in HD, knowledge of the potential implication of other brain regions such as the hippocampus remains limited. Objective Here, we study the comparative impact of enhanced mHTT aggregation and neuropathology in the striatum and hippocampus of two HD mouse models. Methods We utilized the zQ175 as a control HD mouse model and the Q175DN mice lacking the PGK-Neomycin cassette generated in house. We performed a comparative characterization of the neuropathology between zQ175 and Q175DN mice in the striatum and the hippocampus by assessing HTT aggregation, neuronal and glial pathology, chaperone expression, and synaptic density. Results We showed that Q175DN mice presented enhanced mHTT aggregation in both striatum and hippocampus compared to zQ175. Striatal neurons showed a greater susceptibility to enhanced accumulation of mHTT than hippocampal neurons in Q175DN despite high levels of mHTT in both regions. Contrary to the pathology seen in the striatum, Q175DN hippocampus presented enhanced spare capacity showing increased synaptic density, decreased Iba1+ microglia density and enhanced HSF1 levels in specific subregions of the hippocampus compared to zQ175. Conclusions Q175DN mice are a valuable tool to understand the fundamental susceptibility differences to mHTT toxicity between striatal neurons and other neuronal subtypes. Furthermore, our findings also suggest that cognitive deficits observed in HD animals might arise from either striatum dysfunction or other regions involved in cognitive processes but not from hippocampal degeneration.
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Affiliation(s)
- Melissa A Solem
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Ross Pelzel
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Nicholas B. Rozema
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Taylor G. Brown
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Emma Reid
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Rachel H. Mansky
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - R Gomez-Pastor
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Liu Y, Chen X, Ma Y, Song C, Ma J, Chen C, Su J, Ma L, Saiyin H. Endogenous mutant Huntingtin alters the corticogenesis via lowering Golgi recruiting ARF1 in cortical organoid. Mol Psychiatry 2024; 29:3024-3039. [PMID: 38654124 PMCID: PMC11449793 DOI: 10.1038/s41380-024-02562-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/25/2024]
Abstract
Pathogenic mutant huntingtin (mHTT) infiltrates the adult Huntington's disease (HD) brain and impairs fetal corticogenesis. However, most HD animal models rarely recapitulate neuroanatomical alterations in adult HD and developing brains. Thus, the human cortical organoid (hCO) is an alternative approach to decode mHTT pathogenesis precisely during human corticogenesis. Here, we replicated the altered corticogenesis in the HD fetal brain using HD patient-derived hCOs. Our HD-hCOs had pathological phenotypes, including deficient junctional complexes in the neural tubes, delayed postmitotic neuronal maturation, dysregulated fate specification of cortical neuron subtypes, and abnormalities in early HD subcortical projections during corticogenesis, revealing a causal link between impaired progenitor cells and chaotic cortical neuronal layering in the HD brain. We identified novel long, oriented, and enriched polyQ assemblies of HTTs that hold large flat Golgi stacks and scaffold clathrin+ vesicles in the neural tubes of hCOs. Flat Golgi stacks conjugated polyQ assemblies by ADP-ribosylation factor 1 (ARF1). Inhibiting ARF1 activation with Brefeldin A (BFA) disassociated polyQ assemblies from Golgi. PolyQ assembles with mHTT scaffolded fewer ARF1 and formed shorter polyQ assembles with fewer and shorter Golgi and clathrin vesicles in neural tubes of HD-hCOs compared with those in hCOs. Inhibiting the activation of ARF1 by BFA in healthy hCOs replicated impaired junctional complexes in the neural tubes. Together, endogenous polyQ assemblies with mHTT reduced the Golgi recruiting ARF1 in the neuroepithelium, impaired the Golgi structure and activities, and altered the corticogenesis in HD-hCO.
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Affiliation(s)
- Yang Liu
- Department of Anatomy and Histology & Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Xinyu Chen
- Department of Anatomy and Histology & Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Yunlong Ma
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Chenyun Song
- Department of Anatomy and Histology & Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Jixin Ma
- Department of Anatomy and Histology & Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Cheng Chen
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Jianzhong Su
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Lixiang Ma
- Department of Anatomy and Histology & Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
| | - Hexige Saiyin
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, China.
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Mehanna R, Jankovic J. Systemic Symptoms in Huntington's Disease: A Comprehensive Review. Mov Disord Clin Pract 2024; 11:453-464. [PMID: 38529740 PMCID: PMC11078495 DOI: 10.1002/mdc3.14029] [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: 12/02/2023] [Revised: 02/26/2024] [Accepted: 03/12/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND Although Huntington's disease (HD) is usually thought of as a triad of motor, cognitive, and psychiatric symptoms, there is growing appreciation of HD as a systemic illness affecting the entire body. OBJECTIVES This review aims to draw attention to these systemic non-motor symptoms in HD. METHODS We identified relevant studies published in English by searching MEDLINE (from 1966 to September 2023), using the following subject headings: Huntington disease, autonomic, systemic, cardiovascular, respiratory, gastrointestinal, urinary, sexual and cutaneous, and additional specific symptoms. RESULTS Data from 123 articles were critically reviewed with focus on systemic features associated with HD, such as cardiovascular, respiratory, gastrointestinal, urinary, sexual and sweating. CONCLUSION This systematic review draws attention to a variety of systemic and autonomic co-morbidities in patients with HD. Not all of them correlate with the severity of the primary HD symptoms or CAG repeats. More research is needed to better understand the pathophysiology and treatment of systemic and autonomic dysfunction in HD.
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Affiliation(s)
- Raja Mehanna
- Department of NeurologyUniversity of Texas Health Science Center at Houston, McGovern Medical SchoolHoustonTXUSA
| | - Joseph Jankovic
- Parkinson's Disease Center and Movement Disorders Clinic, Department of NeurologyBaylor College of MedicineHoustonTXUSA
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Creus-Muncunill J, Haure-Mirande JV, Mattei D, Bons J, Ramirez AV, Hamilton BW, Corwin C, Chowdhury S, Schilling B, Ellerby LM, Ehrlich ME. TYROBP/DAP12 knockout in Huntington's disease Q175 mice cell-autonomously decreases microglial expression of disease-associated genes and non-cell-autonomously mitigates astrogliosis and motor deterioration. J Neuroinflammation 2024; 21:66. [PMID: 38459557 PMCID: PMC10924371 DOI: 10.1186/s12974-024-03052-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 02/19/2024] [Indexed: 03/10/2024] Open
Abstract
INTRODUCTION Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in the Huntingtin gene (HTT). Immune activation is abundant in the striatum of HD patients. Detection of active microglia at presymptomatic stages suggests that microgliosis is a key early driver of neuronal dysfunction and degeneration. Recent studies showed that deletion of Tyrobp, a microglial protein, ameliorates neuronal dysfunction in Alzheimer's disease amyloidopathy and tauopathy mouse models while decreasing components of the complement subnetwork. OBJECTIVE While TYROBP/DAP12-mediated microglial activation is detrimental for some diseases such as peripheral nerve injury, it is beneficial for other diseases. We sought to determine whether the TYROBP network is implicated in HD and whether Tyrobp deletion impacts HD striatal function and transcriptomics. METHODS To test the hypothesis that Tyrobp deficiency would be beneficial in an HD model, we placed the Q175 HD mouse model on a Tyrobp-null background. We characterized these mice with a combination of behavioral testing, immunohistochemistry, transcriptomic and proteomic profiling. Further, we evaluated the gene signature in isolated Q175 striatal microglia, with and without Tyrobp. RESULTS Comprehensive analysis of publicly available human HD transcriptomic data revealed that the TYROBP network is overactivated in the HD putamen. The Q175 mice showed morphologic microglial activation, reduced levels of post-synaptic density-95 protein and motor deficits at 6 and 9 months of age, all of which were ameliorated on the Tyrobp-null background. Gene expression analysis revealed that lack of Tyrobp in the Q175 model does not prevent the decrease in the expression of striatal neuronal genes but reduces pro-inflammatory pathways that are specifically active in HD human brain, including genes identified as detrimental in neurodegenerative diseases, e.g. C1q and members of the Ccr5 signaling pathway. Integration of transcriptomic and proteomic data revealed that astrogliosis and complement system pathway were reduced after Tyrobp deletion, which was further validated by immunofluorescence analysis. CONCLUSIONS Our data provide molecular and functional support demonstrating that Tyrobp deletion prevents many of the abnormalities in the HD Q175 mouse model, suggesting that the Tyrobp pathway is a potential therapeutic candidate for Huntington's disease.
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Affiliation(s)
| | | | - Daniele Mattei
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Joanna Bons
- Buck Institute for Research on Aging, Novato, CA, USA
| | - Angie V Ramirez
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA
| | - B Wade Hamilton
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Chuhyon Corwin
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Sarah Chowdhury
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA
| | | | | | - Michelle E Ehrlich
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA.
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Bonassi G, Semprini M, Mandich P, Trevisan L, Marchese R, Lagravinese G, Barban F, Pelosin E, Chiappalone M, Mantini D, Avanzino L. Neural oscillations modulation during working memory in pre-manifest and early Huntington's disease. Brain Res 2023; 1820:148540. [PMID: 37598900 DOI: 10.1016/j.brainres.2023.148540] [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: 02/20/2023] [Revised: 07/21/2023] [Accepted: 08/17/2023] [Indexed: 08/22/2023]
Abstract
INTRODUCTION We recently demonstrated specific spectral signatures associated with updating of memory information, working memory (WM) maintenance and readout, with relatively high spatial resolution by means of high-density electroencephalography (hdEEG). WM is impaired already in early symptomatic HD (early-HD) and in pre-manifest HD (pre-HD). The aim of this study was to test whether hdEEG coupled to source localization allows for the identification of neuronal oscillations in specific frequency bands in 16 pre-HD and early-HD during different phases of a WM task. METHODS We examined modulation of neural oscillations by event-related synchronization and desynchronization (ERS/ERD) of θ, β, gamma low, γLOW and γHIGH EEG bands in a-priori selected large fronto-parietal network, including the insula and the cerebellum. RESULTS We found: (i) Reduced θ oscillations in HD with respect to controls in almost all the areas of the WM network during the update and readout phases; (ii) Modulation of β oscillations, which increased during the maintenance phase of the WM task in both groups; (iii) correlation of γHIGH oscillations during WM task with disease burden score in HD patients. CONCLUSIONS Our data show reduced phase-specific modulation of oscillations in pre-HD and early-HD, even in the presence of preserved dynamic of modulation. Particularly, reduced synchronization in the θ band in the areas of the WM network, consistent with abnormal long-range coordination of neuronal activity within this network, was found in update and readout phases in HD groups.
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Affiliation(s)
- Gaia Bonassi
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy
| | - Marianna Semprini
- Rehab Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy
| | - Paola Mandich
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy; IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Lucia Trevisan
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | | | - Giovanna Lagravinese
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy; IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Federico Barban
- Rehab Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Dept. of Informatics, Bioengineering, Robotics and Systems Engineering, University of Genoa, 16145 Genoa, Italy
| | - Elisa Pelosin
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy; IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Michela Chiappalone
- Rehab Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Dept. of Informatics, Bioengineering, Robotics and Systems Engineering, University of Genoa, 16145 Genoa, Italy
| | - Dante Mantini
- Research Center for Motor Control and Neuroplasticity, KU Leuven, 3001 Leuven, Belgium; Brain Imaging and Neural Dynamics Research Group, IRCCS San Camillo Hospital, 30126 Venice, Italy
| | - Laura Avanzino
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; Department of Experimental Medicine, Section of Human Physiology, University of Genoa, 16132 Genoa, Italy.
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Mitra S, Dash R, Nishan AA, Habiba SU, Moon IS. Brain modulation by the gut microbiota: From disease to therapy. J Adv Res 2023; 53:153-173. [PMID: 36496175 PMCID: PMC10658262 DOI: 10.1016/j.jare.2022.12.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/23/2022] [Accepted: 12/01/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The gut microbiota (GM) and brain are strongly associated, which significantly affects neuronal development and disorders. GM-derived metabolites modulate neuronal function and influence many cascades in age-related neurodegenerative disorders (NDDs). Because of the dual role of GM in neuroprotection and neurodegeneration, understanding the balance between beneficial and harmful bacteria is crucial for applying this approach to clinical therapies. AIM OF THE REVIEW This review briefly discusses the role of the gut-brain relationship in promoting brain and cognitive function. Although a healthy gut environment is helpful for brain function, gut dysbiosis can disrupt the brain's environment and create a vicious cycle of degenerative cascades. The ways in which the GM population can affect brain function and the development of neurodegeneration are also discussed. In the treatment and management of NDDs, the beneficial effects of methods targeting GM populations and their derivatives, including probiotics, prebiotics, and fecal microbial transplantation (FMT) are also highlighted. KEY SCIENTIFIC CONCEPT OF THE REVIEW In this review, we aimed to provide a deeper understanding of the mechanisms of the gut microbe-brain relationship and their twin roles in neurodegeneration progression and therapeutic applications. Here, we attempted to highlight the different pathways connecting the brain and gut, together with the role of GM in neuroprotection and neuronal development. Furthermore, potential roles of GM metabolites in the pathogenesis of brain disorders and in strategies for its treatment are also investigated. By analyzing existing in vitro, in vivo and clinical studies, this review attempts to identify new and promising therapeutic strategies for central nervous system (CNS) disorders. As the connection between the gut microbe-brain relationship and responses to NDD treatments is less studied, this review will provide new insights into the global mechanisms of GM modulation in disease progression, and identify potential future perspectives for developing new therapies to treat NDDs.
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Affiliation(s)
- Sarmistha Mitra
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
| | - Amena Al Nishan
- Department of Medicine, Chittagong Medical College, Chittagong 4203, Bangladesh
| | - Sarmin Ummey Habiba
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea.
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Ayyildiz D, Bergonzoni G, Monziani A, Tripathi T, Döring J, Kerschbamer E, Di Leva F, Pennati E, Donini L, Kovalenko M, Zasso J, Conti L, Wheeler VC, Dieterich C, Piazza S, Dassi E, Biagioli M. CAG repeat expansion in the Huntington's disease gene shapes linear and circular RNAs biogenesis. PLoS Genet 2023; 19:e1010988. [PMID: 37831730 PMCID: PMC10617732 DOI: 10.1371/journal.pgen.1010988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 10/31/2023] [Accepted: 09/19/2023] [Indexed: 10/15/2023] Open
Abstract
Alternative splicing (AS) appears to be altered in Huntington's disease (HD), but its significance for early, pre-symptomatic disease stages has not been inspected. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a correlation between Htt CAG repeat length and increased aberrant linear AS, specifically affecting neural progenitors and, in vivo, the striatum prior to overt behavioral phenotypes stages. Remarkably, a significant proportion (36%) of the aberrantly spliced isoforms are not-functional and meant to non-sense mediated decay (NMD). The expanded Htt CAG repeats further reflect on a previously neglected, global impairment of back-splicing, leading to decreased circular RNAs production in neural progenitors. Integrative transcriptomic analyses unveil a network of transcriptionally altered micro-RNAs and RNA-binding proteins (Celf, hnRNPs, Ptbp, Srsf, Upf1, Ythd2) which might influence the AS machinery, primarily in neural cells. We suggest that this unbalanced expression of linear and circular RNAs might alter neural fitness, contributing to HD pathogenesis.
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Affiliation(s)
- Dilara Ayyildiz
- Bioinformatic facility, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
- Biomedical Sciences and Biotechnology, University of Udine, Udine, Italy
| | - Guendalina Bergonzoni
- NeuroEpigenetics laboratory, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Alan Monziani
- NeuroEpigenetics laboratory, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Takshashila Tripathi
- NeuroEpigenetics laboratory, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Jessica Döring
- NeuroEpigenetics laboratory, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Emanuela Kerschbamer
- NeuroEpigenetics laboratory, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Francesca Di Leva
- NeuroEpigenetics laboratory, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Elia Pennati
- NeuroEpigenetics laboratory, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Luisa Donini
- NeuroEpigenetics laboratory, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Marina Kovalenko
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Jacopo Zasso
- Laboratory of Stem Cell Biology, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Luciano Conti
- Laboratory of Stem Cell Biology, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Vanessa C. Wheeler
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Department of Neurology Harvard Medical School, Boston, Massachusetts, United States of America
| | - Christoph Dieterich
- Section of Bioinformatics and Systems Cardiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Silvano Piazza
- Bioinformatic facility, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Erik Dassi
- Laboratory of RNA Regulatory Networks, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
| | - Marta Biagioli
- NeuroEpigenetics laboratory, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy
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11
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D’Egidio F, Castelli V, Cimini A, d’Angelo M. Cell Rearrangement and Oxidant/Antioxidant Imbalance in Huntington's Disease. Antioxidants (Basel) 2023; 12:571. [PMID: 36978821 PMCID: PMC10045781 DOI: 10.3390/antiox12030571] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/17/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Huntington's Disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a CAG triplet repeat in the HTT gene, resulting in the production of an aberrant huntingtin (Htt) protein. The mutant protein accumulation is responsible for neuronal dysfunction and cell death. This is due to the involvement of oxidative damage, excitotoxicity, inflammation, and mitochondrial impairment. Neurons naturally adapt to bioenergetic alteration and oxidative stress in physiological conditions. However, this dynamic system is compromised when a neurodegenerative disorder occurs, resulting in changes in metabolism, alteration in calcium signaling, and impaired substrates transport. Thus, the aim of this review is to provide an overview of the cell's answer to the stress induced by HD, focusing on the role of oxidative stress and its balance with the antioxidant system.
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Affiliation(s)
| | | | | | - Michele d’Angelo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
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12
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Farzana F, McConville MJ, Renoir T, Li S, Nie S, Tran H, Hannan AJ, Hatters DM, Boughton BA. Longitudinal spatial mapping of lipid metabolites reveals pre-symptomatic changes in the hippocampi of Huntington's disease transgenic mice. Neurobiol Dis 2023; 176:105933. [PMID: 36436748 DOI: 10.1016/j.nbd.2022.105933] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/16/2022] [Accepted: 11/23/2022] [Indexed: 11/26/2022] Open
Abstract
In Huntington's disease (HD), a key pathological feature includes the development of inclusion-bodies of fragments of the mutant huntingtin protein in the neurons of the striatum and hippocampus. To examine the molecular changes associated with inclusion-body formation, we applied MALDI-mass spectrometry imaging and deuterium pulse labelling to determine lipid levels and synthesis rates in the hippocampus of a transgenic mouse model of HD (R6/1 line). The R6/1 HD mice lacked inclusions in the hippocampus at 6 weeks of age (pre-symptomatic), whereas inclusions were pervasive by 16 weeks of age (symptomatic). Hippocampal subfields (CA1, CA3 and DG), which formed the highest density of inclusion formation in the mouse brain showed a reduction in the relative abundance of neuron-enriched lipids that have roles in neurotransmission, synaptic plasticity, neurogenesis, and ER-stress protection. Lipids involved in the adaptive response to ER stress (phosphatidylinositol, phosphatidic acid, and ganglioside classes) displayed increased rates of synthesis in HD mice relative to WT mice at all the ages examined, including prior to the formation of the inclusion bodies. Our findings, therefore, support a role for ER stress occurring pre-symptomatically and potentially contributing to pathological mechanisms underlying HD.
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Affiliation(s)
- Farheen Farzana
- Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Victoria 3010, Australia; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
| | - Malcolm J McConville
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia; Metabolomics Australia, The University of Melbourne, Victoria 3010, Australia
| | - Thibault Renoir
- Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Victoria 3010, Australia
| | - Shanshan Li
- Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Victoria 3010, Australia
| | - Shuai Nie
- Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
| | - Harvey Tran
- Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Victoria 3010, Australia
| | - Anthony J Hannan
- Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Victoria 3010, Australia.
| | - Danny M Hatters
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.
| | - Berin A Boughton
- School of Biosciences, The University of Melbourne, Victoria 3010, Australia; Australian National Phenome Centre, Murdoch University, Murdoch 6150, Western Australia, Australia.
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13
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Sun E, Kang M, Wibawa P, Tsoukra V, Chen Z, Farrand S, Eratne D, Kelso W, Evans A, Walterfang M, Velakoulis D, Loi SM. Huntington's disease: Mortality and risk factors in an Australian cohort. J Neurol Sci 2022; 442:120437. [PMID: 36179426 DOI: 10.1016/j.jns.2022.120437] [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: 06/28/2022] [Revised: 09/06/2022] [Accepted: 09/20/2022] [Indexed: 11/29/2022]
Abstract
INTRODUCTION There has not been any examination of the risk factors associated with mortality in Huntington's Disease (HD) in an Australian cohort. METHOD This retrospective study included inpatients admitted to a specialist neuropsychiatry service in Melbourne, Australia. HD status was based on genetic testing. Risk factors included age of onset, CAG repeat length and neuroimaging. Mortality data was acquired through the Australian Institute of Health and Welfare National Death Index. RESULTS The cohort included 83 participants, with 44 (53%) deceased. The median age of death was 59 years and median survival was 18.8 years from onset age (median 41.0 years). CAG repeat length (median 44.0, IQR 42.5, 47.0) was inversely correlated with age of onset (r = -0.73) and age at death (r = -0.80) but was not correlated with mortality status. There was no difference in functional and cognitive assessments, nor brain volumes, in the alive group compared to the deceased group. There were more people who were alive who had a positive family history of a psychiatric condition (p = 0.006) or dementia (p = 0.009). Standardised mortality ratios demonstrated a 5.9× increased risk of death for those with HD compared to the general population. CONCLUSIONS This is the first study to examine risk factors of mortality in HD in an Australian cohort. Median survival in our cohort is consistent with previous studies in HD, and markedly reduced compared to the general Australian population. CAG repeat length was not associated with mortality suggesting that non-genetic factors contribute to mortality status and warrant further investigation.
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Affiliation(s)
- Emily Sun
- Neuropsychiatry, NorthWestern Mental Health, Melbourne Health, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
| | - Matthew Kang
- Neuropsychiatry, NorthWestern Mental Health, Melbourne Health, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
| | - Pierre Wibawa
- Neuropsychiatry, NorthWestern Mental Health, Melbourne Health, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
| | - Vivian Tsoukra
- Department of Neurology, Evaggelismos Hospital, Athens, Greece
| | - Zhibin Chen
- School of Public Health and Preventive Medicine, Monash University, Clayton 3168, Australia.
| | - Sarah Farrand
- Neuropsychiatry, NorthWestern Mental Health, Melbourne Health, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
| | - Dhamidhu Eratne
- Neuropsychiatry, NorthWestern Mental Health, Melbourne Health, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; Department of Psychiatry, The University of Melbourne, Grattan Street, Parkville 3052, Australia; Florey Institute of Neuroscience and Mental Health, Parkville 3052, Australia.
| | - Wendy Kelso
- Neuropsychiatry, NorthWestern Mental Health, Melbourne Health, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
| | - Andrew Evans
- Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
| | - Mark Walterfang
- Neuropsychiatry, NorthWestern Mental Health, Melbourne Health, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; Department of Psychiatry, The University of Melbourne, Grattan Street, Parkville 3052, Australia; Florey Institute of Neuroscience and Mental Health, Parkville 3052, Australia.
| | - Dennis Velakoulis
- Neuropsychiatry, NorthWestern Mental Health, Melbourne Health, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; Department of Psychiatry, The University of Melbourne, Grattan Street, Parkville 3052, Australia.
| | - Samantha M Loi
- Neuropsychiatry, NorthWestern Mental Health, Melbourne Health, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; Department of Psychiatry, The University of Melbourne, Grattan Street, Parkville 3052, Australia.
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14
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Rushmore RJ, Bouix S, Kubicki M, Rathi Y, Yeterian E, Makris N. HOA2.0-ComPaRe: A next generation Harvard-Oxford Atlas comparative parcellation reasoning method for human and macaque individual brain parcellation and atlases of the cerebral cortex. Front Neuroanat 2022; 16:1035420. [PMID: 36439195 PMCID: PMC9684647 DOI: 10.3389/fnana.2022.1035420] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/06/2022] [Indexed: 11/29/2023] Open
Abstract
Comparative structural neuroanatomy is a cornerstone for understanding human brain structure and function. A parcellation framework that relates systematically to fundamental principles of histological organization is an essential step in generating structural comparisons between species. In the present investigation, we developed a comparative parcellation reasoning system (ComPaRe), which is a formal ontological system in human and non-human primate brains based on the cortical cytoarchitectonic mapping used for both species as detailed by Brodmann. ComPaRe provides a theoretical foundation for mapping neural systems in humans and other species using neuroimaging. Based on this approach, we revised the methodology of the original Harvard-Oxford Atlas (HOA) system of brain parcellation to produce a comparative framework for the human (hHOA) and the rhesus monkey (mHOA) brains, which we refer to as HOA2.0-ComPaRe. In addition, we used dedicated segmentation software in the publicly available 3D Slicer platform to parcellate an individual human and rhesus monkey brain. This method produces quantitative morphometric parcellations in the individual brains. Based on these parcellations we created a representative template and 3D brain atlas for the two species, each based on a single subject. Thus, HOA2.0-ComPaRe provides a theoretical foundation for mapping neural systems in humans and other species using neuroimaging, while also representing a significant revision of the original human and macaque monkey HOA parcellation schemas. The methodology and atlases presented here can be used in basic and clinical neuroimaging for morphometric (volumetric) analysis, further generation of atlases, as well as localization of function and structural lesions.
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Affiliation(s)
- Richard Jarrett Rushmore
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, United States
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, MA, United States
- Center for Morphometric Analysis, Massachusetts General Hospital, Boston, MA, United States
| | - Sylvain Bouix
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, MA, United States
- Department of Software Engineering and Information Technology, École de Technologie Supérieure, Montreal, QC, Canada
| | - Marek Kubicki
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, MA, United States
- Center for Morphometric Analysis, Massachusetts General Hospital, Boston, MA, United States
| | - Yogesh Rathi
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, MA, United States
- Center for Morphometric Analysis, Massachusetts General Hospital, Boston, MA, United States
| | - Edward Yeterian
- Center for Morphometric Analysis, Massachusetts General Hospital, Boston, MA, United States
- Department of Psychology, Colby College, Waterville, ME, United States
| | - Nikos Makris
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, United States
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, MA, United States
- Center for Morphometric Analysis, Massachusetts General Hospital, Boston, MA, United States
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15
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Li Y, Li F, Qin D, Chen H, Wang J, Wang J, Song S, Wang C, Wang Y, Liu S, Gao D, Wang ZH. The role of brain derived neurotrophic factor in central nervous system. Front Aging Neurosci 2022; 14:986443. [PMID: 36158555 PMCID: PMC9493475 DOI: 10.3389/fnagi.2022.986443] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/23/2022] [Indexed: 11/15/2022] Open
Abstract
Brain derived neurotrophic factor (BDNF) has multiple biological functions which are mediated by the activation of two receptors, tropomyosin receptor kinase B (TrkB) receptor and the p75 neurotrophin receptor, involving in physiological and pathological processes throughout life. The diverse presence and activity of BDNF indicate its potential role in the pathogenesis, progression and treatment of both neurological and psychiatric disorders. This review is to provide a comprehensive assessment of the current knowledge and future directions in BDNF-associated research in the central nervous system (CNS), with an emphasis on the physiological and pathological functions of BDNF as well as its potential treatment effects in CNS diseases, including depression, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cerebral ischemic stroke.
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Affiliation(s)
- Yiyi Li
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fang Li
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Dongdong Qin
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hongyu Chen
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jianhao Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jiabei Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shafei Song
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chao Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yamei Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Songyan Liu
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Dandan Gao
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhi-Hao Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
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16
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Singh A, Agrawal N. Metabolism in Huntington's disease: a major contributor to pathology. Metab Brain Dis 2022; 37:1757-1771. [PMID: 34704220 DOI: 10.1007/s11011-021-00844-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/15/2021] [Indexed: 01/01/2023]
Abstract
Huntington's disease (HD) is a progressively debilitating neurodegenerative disease exhibiting autosomal-dominant inheritance. It is caused by an unstable expansion in the CAG repeat tract of HD gene, which transforms the disease-specific Huntingtin protein (HTT) to a mutant form (mHTT). The profound neuronal death in cortico-striatal circuits led to its identification and characterisation as a neurodegenerative disease. However, equally disturbing are the concomitant whole-body manifestations affecting nearly every organ of the diseased individuals, at varying extents. Altered central and peripheral metabolism of energy, proteins, nucleic acids, lipids and carbohydrates encompass the gross pathology of the disease. Intense fluctuation of body weight, glucose homeostasis and organ-specific subcellular abnormalities are being increasingly recognised in HD. Many of these metabolic abnormalities exist years before the neuropathological manifestations such as chorea, cognitive decline and behavioural abnormalities develop, and prove to be reliable predictors of the disease progression. In this review, we provide a consolidated overview of the central and peripheral metabolic abnormalities associated with HD, as evidenced from clinical and experimental studies. Additionally, we have discussed the potential of metabolic biomolecules to translate into efficient biomarkers for the disease onset as well as progression. Finally, we provide a brief outlook on the efficacy of existing therapies targeting metabolic remediation. While it is clear that components of altered metabolic pathways can mark many aspects of the disease, it is only conceivable that combinatorial therapies aiming for neuronal protection in consort with metabolic upliftment will prove to be more efficient than the existing symptomatic treatment options.
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Affiliation(s)
- Akanksha Singh
- Department of Zoology, University of Delhi, New Delhi, 110007, India
| | - Namita Agrawal
- Department of Zoology, University of Delhi, New Delhi, 110007, India.
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17
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Temporal Characterization of Behavioral and Hippocampal Dysfunction in the YAC128 Mouse Model of Huntington’s Disease. Biomedicines 2022; 10:biomedicines10061433. [PMID: 35740454 PMCID: PMC9219853 DOI: 10.3390/biomedicines10061433] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/09/2022] [Accepted: 06/14/2022] [Indexed: 11/17/2022] Open
Abstract
Huntington’s disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal characterization of the behavioral and hippocampal dysfunctions. Early and late symptomatic YAC128 mice exhibited depressive-like behavior, as demonstrated by increased immobility times in the Tail Suspension Test. In addition, YAC128 mice exhibited cognitive deficits in the Swimming T-maze Test during the late symptomatic stage. Except for a reduction in basal mitochondrial respiration, no significant deficits in the mitochondrial respiratory rates were observed in the hippocampus of late symptomatic YAC128 mice. In agreement, YAC128 animals did not present robust alterations in mitochondrial ultrastructural morphology. However, light and electron microscopy analysis revealed the presence of dark neurons characterized by the intense staining of granule cell bodies and shrunken nuclei and cytoplasm in the hippocampal dentate gyrus (DG) of late symptomatic YAC128 mice. Furthermore, structural alterations in the rough endoplasmic reticulum and Golgi apparatus were detected in the hippocampal DG of YAC128 mice by electron microscopy. These results clearly show a degenerative process in the hippocampal DG in late symptomatic YAC128 animals.
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18
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Li SH, Colson TLL, Abd-Elrahman KS, Ferguson SSG. Metabotropic Glutamate Receptor 5 Antagonism Reduces Pathology and Differentially Improves Symptoms in Male and Female Heterozygous zQ175 Huntington’s Mice. Front Mol Neurosci 2022; 15:801757. [PMID: 35185467 PMCID: PMC8847794 DOI: 10.3389/fnmol.2022.801757] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/07/2022] [Indexed: 12/11/2022] Open
Abstract
Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disorder that leads to progressive motor and cognitive impairment. There are currently no available disease modifying treatments for HD patients. We have previously shown that pharmacological blockade of metabotropic glutamate receptor 5 (mGluR5) signaling rescues motor deficits, improves cognitive impairments and mitigates HD neuropathology in male zQ175 HD mice. Mounting evidence indicates that sex may influence HD progression and we have recently reported a sex-specific pathological mGluR5 signaling in Alzheimer’s disease (AD) mice. Here, we compared the outcomes of treatment with the mGluR5 negative allosteric modulator CTEP (2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4-yl]ethynyl]pyridine) in both male and female symptomatic zQ175 mice. We found that female zQ175 mice required a longer treatment duration with CTEP than male mice to show improvement in their rotarod performance. Unlike males, chronic CTEP treatment did not improve the grip strength nor reverse the cognitive decline of female zQ175 mice. However, CTEP reduced the number of huntingtin aggregates, improved neuronal survival and decreased microglia activation in the striatum of both male and female zQ175 mice. Together, our results indicate that mGluR5 antagonism can reduce HD neuropathology in both male and female zQ175 HD mice, but sex has a clear impact on the efficacy of the treatment and must be taken into consideration for future HD drug development.
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Affiliation(s)
- Si Han Li
- Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Tash-Lynn L. Colson
- Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Khaled S. Abd-Elrahman
- Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Stephen S. G. Ferguson
- Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- *Correspondence: Stephen S. G. Ferguson,
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19
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Pérez-Sisqués L, Solana-Balaguer J, Campoy-Campos G, Martín-Flores N, Sancho-Balsells A, Vives-Isern M, Soler-Palazón F, Garcia-Forn M, Masana M, Alberch J, Pérez-Navarro E, Giralt A, Malagelada C. RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington's Disease. Biomolecules 2021; 12:34. [PMID: 35053183 PMCID: PMC8773874 DOI: 10.3390/biom12010034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/21/2021] [Accepted: 12/24/2021] [Indexed: 12/03/2022] Open
Abstract
RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples, and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction in inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease.
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Affiliation(s)
- Leticia Pérez-Sisqués
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
| | - Júlia Solana-Balaguer
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
| | - Genís Campoy-Campos
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
| | - Núria Martín-Flores
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
| | - Anna Sancho-Balsells
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
| | - Marcel Vives-Isern
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
| | - Ferran Soler-Palazón
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
| | - Marta Garcia-Forn
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
| | - Mercè Masana
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
| | - Jordi Alberch
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Esther Pérez-Navarro
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
| | - Albert Giralt
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Cristina Malagelada
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; (L.P.-S.); (J.S.-B.); (G.C.-C.); (N.M.-F.); (A.S.-B.); (M.V.-I.); (F.S.-P.); (M.G.-F.); (M.M.); (J.A.); (E.P.-N.)
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
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20
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Kaye J, Reisine T, Finkbeiner S. Huntington's disease mouse models: unraveling the pathology caused by CAG repeat expansion. Fac Rev 2021; 10:77. [PMID: 34746930 PMCID: PMC8546598 DOI: 10.12703/r/10-77] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Huntington's disease (HD) is a neurodegenerative disease that results in motor and cognitive dysfunction, leading to early death. HD is caused by an expansion of CAG repeats in the huntingtin gene (HTT). Here, we review the mouse models of HD. They have been used extensively to better understand the molecular and cellular basis of disease pathogenesis as well as to provide non-human subjects to test the efficacy of potential therapeutics. The first and best-studied in vivo rodent model of HD is the R6/2 mouse, in which a transgene containing the promoter and exon 1 fragment of human HTT with 150 CAG repeats was inserted into the mouse genome. R6/2 mice express rapid, robust behavioral pathologies and display a number of degenerative abnormalities in neuronal populations most vulnerable in HD. The first conditional full-length mutant huntingtin (mHTT) mouse model of HD was the bacterial artificial chromosome (BAC) transgenic mouse model of HD (BACHD), which expresses human full-length mHTT with a mixture of 97 CAG-CAA repeats under the control of endogenous HTT regulatory machinery. It has been useful in identifying the role of mHTT in specific neuronal populations in degenerative processes. In the knock-in (KI) model of HD, the expanded human CAG repeats and human exon 1 are inserted into the mouse Htt locus, so a chimera of the full-length mouse protein with the N-terminal human portion is expressed. Many of aspects of the pathology and behavioral deficits in the KI model better mimic disease characteristics found in HD patients than other models. Accordingly, some have proposed that these mice may be preferable models of the disease over others. Indeed, as our understanding of HD advances, so will the design of animal models to test and develop HD therapies.
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Affiliation(s)
- Julia Kaye
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA, USA
| | - Terry Reisine
- Independent Scientific Consultant, Santa Cruz, CA, USA
| | - Steve Finkbeiner
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA, USA
- Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA, USA
- Department of Neurology and Physiology, University of California, San Francisco, CA, USA
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21
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Delva A, Michiels L, Koole M, Van Laere K, Vandenberghe W. Synaptic Damage and Its Clinical Correlates in People With Early Huntington Disease: A PET Study. Neurology 2021; 98:e83-e94. [PMID: 34663644 DOI: 10.1212/wnl.0000000000012969] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 10/04/2021] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Synaptic damage has been proposed to play a major role in the pathophysiology of Huntington's disease (HD), but in vivo evidence in humans is lacking. We performed a PET imaging study to assess synaptic damage and its clinical correlates in early HD in vivo. METHODS: In this cross-sectional study, premanifest and early manifest (Shoulson-Fahn stage 1 and 2) HD mutation carriers and age- and gender-matched healthy controls underwent clinical assessment of motor and non-motor manifestations and time-of-flight PET with 11C-UCB-J, a radioligand targeting the ubiquitous presynaptic terminal marker SV2A. We also performed 18F-FDG PET in all subjects, as regional cerebral glucose consumption is thought to largely reflect synaptic activity. Volumes of interest were delineated based on individual 3D T1 MRI. Standardized uptake value ratio (SUVR)-1 images were calculated for 11C-UCB-J with the centrum semiovale as reference region. 18F-FDG PET activity was normalized to the pons. All PET data were corrected for partial volume effects. Volume of interest- and voxel-based analyses were performed. Correlations between clinical scores and 11C-UCB-J PET data were calculated. RESULTS 18 HD mutation carriers (51.4 ± 11.6 years; 6 female; 7 premanifest, 11 early manifest) and 15 healthy controls (52.3 ± 3.5 years; 4 female) were included. In the HD group, significant loss of SV2A binding was found in putamen, caudate, pallidum, cerebellum, parietal, temporal and frontal cortex, whereas reduced 18F-FDG uptake was restricted to caudate and putamen. In the premanifest subgroup, 11C-UCB-J and 18F-FDG PET showed significant reductions in putamen and caudate only. In the total HD group, SV2A loss in the putamen correlated with motor impairment. DISCUSSION Our data reveal loss of presynaptic terminal integrity in early HD, which begins in the striatum in the premanifest phase, spreads extensively to extrastriatal regions in the early manifest phase, and correlates with motor impairment. 11C-UCB-J PET is more sensitive than 18F-FDG PET for detection of extrastriatal changes in early HD. CLASSIFICATION OF EVIDENCE This study provides class III evidence that 11C-UCB-J PET accurately identifies HD from normal controls.
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Affiliation(s)
- Aline Delva
- Department of Neurosciences, KU Leuven, Belgium; .,Department of Neurology, University Hospitals Leuven, Belgium
| | - Laura Michiels
- Department of Neurosciences, KU Leuven, Belgium.,Department of Neurology, University Hospitals Leuven, Belgium.,VIB, Center for Brain & Disease Research, Belgium
| | - Michel Koole
- Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Belgium
| | - Koen Van Laere
- Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Belgium.,Division of Nuclear Medicine, University Hospitals Leuven, Belgium
| | - Wim Vandenberghe
- Department of Neurosciences, KU Leuven, Belgium.,Department of Neurology, University Hospitals Leuven, Belgium
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22
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Chiki A, Zhang Z, Rajasekhar K, Abriata LA, Rostami I, Krapp LF, Boudeffa D, Dal Peraro M, Lashuel HA. Investigating Crosstalk Among PTMs Provides Novel Insight Into the Structural Basis Underlying the Differential Effects of Nt17 PTMs on Mutant Httex1 Aggregation. Front Mol Biosci 2021; 8:686086. [PMID: 34381813 PMCID: PMC8352439 DOI: 10.3389/fmolb.2021.686086] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 07/06/2021] [Indexed: 01/24/2023] Open
Abstract
Post-translational modifications (PTMs) within the first 17 amino acids (Nt17) of the Huntingtin protein (Htt) have been shown to inhibit the aggregation and attenuate the toxicity of mutant Htt proteins in vitro and in various models of Huntington’s disease. Here, we expand on these studies by investigating the effect of methionine eight oxidation (oxM8) and its crosstalk with lysine 6 acetylation (AcK6) or threonine 3 phosphorylation (pT3) on the aggregation of mutant Httex1 (mHttex1). We show that M8 oxidation delays but does not inhibit the aggregation and has no effect on the final morphologies of mHttex1aggregates. The presence of both oxM8 and AcK6 resulted in dramatic inhibition of Httex1 fibrillization. Circular dichroism spectroscopy and molecular dynamics simulation studies show that PTMs that lower the mHttex1 aggregation rate (oxM8, AcK6/oxM8, pT3, pT3/oxM8, and pS13) result in increased population of a short N-terminal helix (first eight residues) in Nt17 or decreased abundance of other helical forms, including long helix and short C-terminal helix. PTMs that did not alter the aggregation rate (AcK6) of mHttex1 exhibit a similar distribution of helical conformation as the unmodified peptides. These results show that the relative abundance of N- vs. C-terminal helical conformations and long helices, rather than the overall helicity of Nt17, better explains the effect of different Nt17 PTMs on mHttex1; thus, explaining the lack of correlation between the effect of PTMs on the overall helicity of Nt17 and mHttex1 aggregation in vitro. Taken together, our results provide novel structural insight into the differential effects of single PTMs and crosstalk between different PTMs in regulating mHttex1 aggregation.
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Affiliation(s)
- Anass Chiki
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Zhidian Zhang
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.,Laboratory for Biomolecular Modeling, School of Life Sciences, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Kolla Rajasekhar
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Luciano A Abriata
- Laboratory for Biomolecular Modeling, School of Life Sciences, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Iman Rostami
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.,Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland
| | - Lucien F Krapp
- Laboratory for Biomolecular Modeling, School of Life Sciences, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Driss Boudeffa
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Matteo Dal Peraro
- Laboratory for Biomolecular Modeling, School of Life Sciences, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Hilal A Lashuel
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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23
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Barron JC, Hurley EP, Parsons MP. Huntingtin and the Synapse. Front Cell Neurosci 2021; 15:689332. [PMID: 34211373 PMCID: PMC8239291 DOI: 10.3389/fncel.2021.689332] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022] Open
Abstract
Huntington disease (HD) is a monogenic disease that results in a combination of motor, psychiatric and cognitive symptoms. HD is caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which results in the production of a pathogenic mutant HTT protein (mHTT). Although there is no cure at present for HD, a number of RNA-targeting therapies have recently entered clinical trials which aim to lower mHTT production through the use of antisense oligonucleotides (ASOs) and RNAi. However, many of these treatment strategies are non-selective in that they cannot differentiate between non-pathogenic wild type HTT (wtHTT) and the mHTT variant. As HD patients are already born with decreased levels of wtHTT, these genetic therapies may result in critically low levels of wtHTT. The consequence of wtHTT reduction in the adult brain is currently under debate, and here we argue that wtHTT loss is not well-tolerated at the synaptic level. Synaptic dysfunction is an extremely sensitive measure of subsequent cell death, and is known to precede neurodegeneration in numerous brain diseases including HD. The present review focuses on the prominent role of wtHTT at the synapse and considers the consequences of wtHTT loss on both pre- and postsynaptic function. We discuss how wtHTT is implicated in virtually all major facets of synaptic neurotransmission including anterograde and retrograde transport of proteins to/from terminal buttons and dendrites, neurotransmitter release, endocytic vesicle recycling, and postsynaptic receptor localization and recycling. We conclude that wtHTT presence is essential for proper synaptic function.
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Affiliation(s)
- Jessica C Barron
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, NL, Canada
| | - Emily P Hurley
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, NL, Canada
| | - Matthew P Parsons
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, NL, Canada
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24
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When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer's and Huntington's Disease. Int J Mol Sci 2021; 22:ijms22115911. [PMID: 34072862 PMCID: PMC8199025 DOI: 10.3390/ijms22115911] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 01/18/2023] Open
Abstract
Alzheimer's disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington's disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.
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25
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Huntington's disease brain-derived small RNAs recapitulate associated neuropathology in mice. Acta Neuropathol 2021; 141:565-584. [PMID: 33547932 DOI: 10.1007/s00401-021-02272-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 12/18/2022]
Abstract
Progressive motor alterations and selective death of striatal medium spiny neurons (MSNs) are key pathological hallmarks of Huntington's disease (HD), a neurodegenerative condition caused by a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene. Most research has focused on the pathogenic effects of the resultant protein product(s); however, growing evidence indicates that expanded CAG repeats within mutant HTT mRNA and derived small CAG repeat RNAs (sCAG) participate in HD pathophysiology. The individual contribution of protein versus RNA toxicity to HD pathophysiology remains largely uncharacterized and the role of other classes of small RNAs (sRNA) that are strongly perturbed in HD is uncertain. Here, we demonstrate that sRNA produced in the putamen of HD patients (HD-sRNA-PT) are sufficient to induce HD pathology in vivo. Mice injected with HD-sRNA-PT show motor abnormalities, decreased levels of striatal HD-related proteins, disruption of the indirect pathway, and strong transcriptional abnormalities, paralleling human HD pathology. Importantly, we show that the specific blockage of sCAG mitigates HD-sRNA-PT neurotoxicity only to a limited extent. This observation prompted us to identify other sRNA species enriched in HD putamen with neurotoxic potential. We detected high levels of tRNA fragments (tRFs) in HD putamen, and we validated the neurotoxic potential of an Alanine derived tRF in vitro. These results highlight that HD-sRNA-PT are neurotoxic, and suggest that multiple sRNA species contribute to striatal dysfunction and general transcriptomic changes, favoring therapeutic strategies based on the blockage of sRNA-mediated toxicity.
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26
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Simmons DA, Mills BD, Butler Iii RR, Kuan J, McHugh TLM, Akers C, Zhou J, Syriani W, Grouban M, Zeineh M, Longo FM. Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington's Disease: Preclinical Evidence with the p75 NTR Ligand LM11A-31. Neurotherapeutics 2021; 18:1039-1063. [PMID: 33786806 PMCID: PMC8423954 DOI: 10.1007/s13311-021-01023-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2021] [Indexed: 12/13/2022] Open
Abstract
Huntington's disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.
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Affiliation(s)
- Danielle A Simmons
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
| | - Brian D Mills
- Department of Radiology, Stanford University Medical Center, Stanford, CA, 94305, USA
| | - Robert R Butler Iii
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Jason Kuan
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Tyne L M McHugh
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Carolyn Akers
- Department of Radiology, Stanford University Medical Center, Stanford, CA, 94305, USA
| | - James Zhou
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Wassim Syriani
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Maged Grouban
- Department of Radiology, Stanford University Medical Center, Stanford, CA, 94305, USA
| | - Michael Zeineh
- Department of Radiology, Stanford University Medical Center, Stanford, CA, 94305, USA
| | - Frank M Longo
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
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27
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Schultz JL, Harshman LA, Kamholz JA, Nopoulos PC. Autonomic dysregulation as an early pathologic feature of Huntington Disease. Auton Neurosci 2021; 231:102775. [PMID: 33571915 PMCID: PMC8176778 DOI: 10.1016/j.autneu.2021.102775] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 10/22/2022]
Abstract
OBJECTIVE Autonomic nervous system (ANS) dysfunction has been described in adults with motor-manifest Huntington's Disease (HD) or those who are near their predicted motor onset. It is unclear if ANS dysfunction is present years prior to the onset of motor symptoms of HD. To bridge this gap in knowledge, we compared crude markers of ANS function between children with the gene-expansion that causes HD (GE group) who were decades from their predicted motor onset and gene-non-expanded children (GNE group). METHODS We included participants from the Kids-HD study who were <18 years old. Linear mixed effects regression models were constructed that controlled for sex, age, and BMI, and included a random effect per participant and per family. We compared resting heart rate (rHR), core body temperature (CBT), systolic blood pressure (SBP), and diastolic blood pressure (DBP) between the GE (n = 84) and GNE (n = 238) groups. We then grouped participants from the GE group based on their predicted years to onset (YTO) and compared their vital signs to the GNE group. RESULTS The GE group had higher rHR (∆ = 3.83, p = 0.0064), SBP (∆ = 2.38, p = 0.032), and CBT (∆ = 0.16, t = 2.92, p = 0.007). The mean rHR and CBT became significantly elevated compared to the GNE group in participants who had 15-25 YTO and those who had <15 YTO. The mean SBP of participants who had 25-35 YTO was significantly elevated compared to the GNE group. CONCLUSION ANS dysfunction in HD seems to occur approximately 20 years prior to the predicted onset of motor symptoms of HD.
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Affiliation(s)
- Jordan L Schultz
- Department of Psychiatry, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA; Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA; University of Iowa College of Pharmacy, Iowa City, IA, USA.
| | - Lyndsay A Harshman
- Stead Family Children's Hospital at the University of Iowa, Iowa City, IA, USA.
| | - John A Kamholz
- Department of Psychiatry, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA; Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA.
| | - Peg C Nopoulos
- Department of Psychiatry, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA; Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA; Stead Family Children's Hospital at the University of Iowa, Iowa City, IA, USA.
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Franco-Iborra S, Plaza-Zabala A, Montpeyo M, Sebastian D, Vila M, Martinez-Vicente M. Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease. Autophagy 2021; 17:672-689. [PMID: 32093570 PMCID: PMC8032238 DOI: 10.1080/15548627.2020.1728096] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 01/27/2020] [Accepted: 02/04/2020] [Indexed: 12/13/2022] Open
Abstract
The precise degradation of dysfunctional mitochondria by mitophagy is essential for maintaining neuronal homeostasis. HTT (huntingtin) can interact with numerous other proteins and thereby perform multiple biological functions within the cell. In this study, we investigated the role of HTT during mitophagy and analyzed the impact of the expansion of its polyglutamine (polyQ) tract. HTT is involved in different mitophagy steps, promoting the physical proximity of different protein complexes during the initiation of mitophagy and recruiting mitophagy receptors essential for promoting the interaction between damaged mitochondria and the nascent autophagosome. The presence of the polyQ tract in mutant HTT affects the formation of these protein complexes and determines the negative consequences of mutant HTT on mitophagy, leading to the accumulation of damaged mitochondria and an increase in oxidative stress. These outcomes contribute to general mitochondrial dysfunction and neurodegeneration in Huntington disease.Abbreviations: AMPK: AMP-activated protein kinase; ATG13: autophagy related 13; BECN1: beclin 1, autophagy related; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chlorophenyl hydrazone; DMEM: Dulbecco's modified eagle medium; EDTA: ethylene-diamine-tetra-acetic acid; EGFP: enhanced green fluorescent protein; EGTA: ethylene glycol bis(2-aminoethyl ether)tetraacetic acid; FUNDC1: FUN14 domain containing 1; HD: Huntington disease; HRP: horseradish peroxidase; HTT: huntingtin; LC3-II: lipidated form of MAP1LC3/LC3; mtDNA: mitochondrial deoxyribonucleic acid; MTDR: MitoTracker Deep Red; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1, autophagy cargo receptor; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; OCR: oxygen consumption rate; OPTN: optineurin; OXPHOS: oxidative phosphorylation; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PINK1: PTEN induced putative kinase 1; PLA: proximity ligation assay; PMSF: phenylmethylsulfonyl fluoride; polyQ: polyglutamine; PtdIns3K: phosphatidylinositol 3-kinase; ROS: reactive oxygen species; Rot: rotenone; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TMRM: tetramethylrhodamine methyl ester; UB: ubiquitin; ULK1: unc-51 like kinase 1.
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Affiliation(s)
- Sandra Franco-Iborra
- Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED)-Autonomous University of Barcelona, Barcelona, Spain
| | - Ainhoa Plaza-Zabala
- Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED)-Autonomous University of Barcelona, Barcelona, Spain
| | - Marta Montpeyo
- Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED)-Autonomous University of Barcelona, Barcelona, Spain
| | - David Sebastian
- Institute for Research in Biomedicine (IRB) - Diabetes and Associated Metabolic Diseases Networking Biomedical Research (CIBERDEM), Barcelona, Spain
| | - Miquel Vila
- Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED)-Autonomous University of Barcelona, Barcelona, Spain
- Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Marta Martinez-Vicente
- Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED)-Autonomous University of Barcelona, Barcelona, Spain
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29
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Shacham T, Patel C, Lederkremer GZ. PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate? Biomolecules 2021; 11:biom11030354. [PMID: 33652720 PMCID: PMC7996871 DOI: 10.3390/biom11030354] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/18/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
With the extension of life span in recent decades, there is an increasing burden of late-onset neurodegenerative diseases, for which effective treatments are lacking. Neurodegenerative diseases include the widespread Alzheimer’s disease (AD) and Parkinson’s disease (PD), the less frequent Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS) and also rare early-onset diseases linked to mutations that cause protein aggregation or loss of function in genes that maintain protein homeostasis. The difficulties in applying gene therapy approaches to tackle these diseases is drawing increasing attention to strategies that aim to inhibit cellular toxicity and restore homeostasis by intervening in cellular pathways. These include the unfolded protein response (UPR), activated in response to endoplasmic reticulum (ER) stress, a cellular affliction that is shared by these diseases. Special focus is turned to the PKR-like ER kinase (PERK) pathway of the UPR as a target for intervention. However, the complexity of the pathway and its ability to promote cell survival or death, depending on ER stress resolution, has led to some confusion in conflicting studies. Both inhibition and activation of the PERK pathway have been reported to be beneficial in disease models, although there are also some reports where they are counterproductive. Although with the current knowledge a definitive answer cannot be given on whether it is better to activate or to inhibit the pathway, the most encouraging strategies appear to rely on boosting some steps without compromising downstream recovery.
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Affiliation(s)
- Talya Shacham
- Cell Biology Division, George Wise Faculty of Life Sciences, The Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv 69978, Israel; (T.S.); (C.P.)
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
| | - Chaitanya Patel
- Cell Biology Division, George Wise Faculty of Life Sciences, The Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv 69978, Israel; (T.S.); (C.P.)
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
| | - Gerardo Z. Lederkremer
- Cell Biology Division, George Wise Faculty of Life Sciences, The Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv 69978, Israel; (T.S.); (C.P.)
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
- Correspondence: ; Tel.: +972-3-640-9239
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van Oostveen WM, de Lange ECM. Imaging Techniques in Alzheimer's Disease: A Review of Applications in Early Diagnosis and Longitudinal Monitoring. Int J Mol Sci 2021; 22:ijms22042110. [PMID: 33672696 PMCID: PMC7924338 DOI: 10.3390/ijms22042110] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting many individuals worldwide with no effective treatment to date. AD is characterized by the formation of senile plaques and neurofibrillary tangles, followed by neurodegeneration, which leads to cognitive decline and eventually death. INTRODUCTION In AD, pathological changes occur many years before disease onset. Since disease-modifying therapies may be the most beneficial in the early stages of AD, biomarkers for the early diagnosis and longitudinal monitoring of disease progression are essential. Multiple imaging techniques with associated biomarkers are used to identify and monitor AD. AIM In this review, we discuss the contemporary early diagnosis and longitudinal monitoring of AD with imaging techniques regarding their diagnostic utility, benefits and limitations. Additionally, novel techniques, applications and biomarkers for AD research are assessed. FINDINGS Reduced hippocampal volume is a biomarker for neurodegeneration, but atrophy is not an AD-specific measure. Hypometabolism in temporoparietal regions is seen as a biomarker for AD. However, glucose uptake reflects astrocyte function rather than neuronal function. Amyloid-β (Aβ) is the earliest hallmark of AD and can be measured with positron emission tomography (PET), but Aβ accumulation stagnates as disease progresses. Therefore, Aβ may not be a suitable biomarker for monitoring disease progression. The measurement of tau accumulation with PET radiotracers exhibited promising results in both early diagnosis and longitudinal monitoring, but large-scale validation of these radiotracers is required. The implementation of new processing techniques, applications of other imaging techniques and novel biomarkers can contribute to understanding AD and finding a cure. CONCLUSIONS Several biomarkers are proposed for the early diagnosis and longitudinal monitoring of AD with imaging techniques, but all these biomarkers have their limitations regarding specificity, reliability and sensitivity. Future perspectives. Future research should focus on expanding the employment of imaging techniques and identifying novel biomarkers that reflect AD pathology in the earliest stages.
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Affiliation(s)
- Wieke M. van Oostveen
- Faculty of Science, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands;
| | - Elizabeth C. M. de Lange
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre of Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
- Correspondence: ; Tel.: +31-71-527-6330
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Hecklau K, Mueller S, Koch SP, Mehkary MH, Kilic B, Harms C, Boehm-Sturm P, Yildirim F. The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington's Disease Mice. Front Mol Neurosci 2021; 14:616886. [PMID: 33679321 PMCID: PMC7925995 DOI: 10.3389/fnmol.2021.616886] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 01/27/2021] [Indexed: 01/15/2023] Open
Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes Neurod2 and Nr4a2, and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD.
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Affiliation(s)
- Katharina Hecklau
- Department of Neuropsychiatry, Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Berlin, Germany
- NeuroCure Cluster of Excellence, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Susanne Mueller
- NeuroCure Cluster of Excellence, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Charité Core Facility 7T Experimental MRIs, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Paul Koch
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Charité Core Facility 7T Experimental MRIs, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Mustafa Hussain Mehkary
- Department of Neuropsychiatry, Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Berlin, Germany
- NeuroCure Cluster of Excellence, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Busra Kilic
- Department of Neuropsychiatry, Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Berlin, Germany
- NeuroCure Cluster of Excellence, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Christoph Harms
- NeuroCure Cluster of Excellence, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Einstein Center for Neurosciences Berlin, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Philipp Boehm-Sturm
- NeuroCure Cluster of Excellence, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Charité Core Facility 7T Experimental MRIs, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Ferah Yildirim
- Department of Neuropsychiatry, Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Berlin, Germany
- NeuroCure Cluster of Excellence, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Einstein Center for Neurosciences Berlin, Charité – Universitätsmedizin Berlin, Berlin, Germany
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Voysey Z, Fazal SV, Lazar AS, Barker RA. The sleep and circadian problems of Huntington's disease: when, why and their importance. J Neurol 2020; 268:2275-2283. [PMID: 33355880 PMCID: PMC8179890 DOI: 10.1007/s00415-020-10334-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/15/2020] [Accepted: 11/19/2020] [Indexed: 11/30/2022]
Abstract
Introduction Mounting evidence supports the existence of an important feedforward cycle between sleep and neurodegeneration, wherein neurodegenerative diseases cause sleep and circadian abnormalities, which in turn exacerbate and accelerate neurodegeneration. If so, sleep therapies bear important potential to slow progression in these diseases. Findings This cycle is challenging to study, as its bidirectional nature renders cause difficult to disentangle from effect. Likewise, well-controlled intervention studies are often impractical in the setting of established neurodegenerative disease. It is this that makes understanding sleep and circadian abnormalities in Huntington’s disease (HD) important: as a monogenic fully penetrant neurodegenerative condition presenting in midlife, it provides a rare opportunity to study sleep and circadian abnormalities longitudinally, prior to and throughout disease manifestation, and in the absence of confounds rendered by age and comorbidities. It also provides potential to trial sleep therapies at a preclinical or early disease stage. Moreover, its monogenic nature facilitates the development of transgenic animal models through which to run parallel pre-clinical studies. HD, therefore, provides a key model condition through which to gain new insights into the sleep-neurodegeneration interface. Conclusions Here, we begin by summarising contemporary knowledge of sleep abnormalities in HD, and consider how well these parallel those of Alzheimer’s and Parkinson’s as more common neurodegenerative conditions. We then discuss what is currently known of the sleep-neurodegeneration cyclical relationship in HD. We conclude by outlining key directions of current and future investigation by which to advance the sleep-neurodegeneration field via studies in HD.
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Affiliation(s)
- Z Voysey
- Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
| | - S V Fazal
- Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
| | - A S Lazar
- Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
| | - R A Barker
- Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, WT-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
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Tan B, Shishegar R, Poudel GR, Fornito A, Georgiou-Karistianis N. Cortical morphometry and neural dysfunction in Huntington's disease: a review. Eur J Neurol 2020; 28:1406-1419. [PMID: 33210786 DOI: 10.1111/ene.14648] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/22/2020] [Accepted: 11/12/2020] [Indexed: 01/09/2023]
Abstract
Numerous neuroimaging techniques have been used to identify biomarkers of disease progression in Huntington's disease (HD). To date, the earliest and most sensitive of these is caudate volume; however, it is becoming increasingly evident that numerous changes to cortical structures, and their interconnected networks, occur throughout the course of the disease. The mechanisms by which atrophy spreads from the caudate to these cortical regions remains unknown. In this review, the neuroimaging literature specific to T1-weighted and diffusion-weighted magnetic resonance imaging is summarized and new strategies for the investigation of cortical morphometry and the network spread of degeneration in HD are proposed. This new avenue of research may enable further characterization of disease pathology and could add to a suite of biomarker/s of disease progression for patient stratification that will help guide future clinical trials.
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Affiliation(s)
- Brendan Tan
- School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia
| | - Rosita Shishegar
- School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia.,Australian e-Health Research Centre, CSIRO, Melbourne, VIC, Australia.,Monash Biomedical Imaging, Melbourne, VIC, Australia
| | - Govinda R Poudel
- School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia.,Sydney Imaging, Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.,Australian Catholic University, Melbourne, VIC, Australia
| | - Alex Fornito
- School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia.,Monash Biomedical Imaging, Melbourne, VIC, Australia
| | - Nellie Georgiou-Karistianis
- School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia
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Cepeda C, Levine MS. Synaptic Dysfunction in Huntington's Disease: Lessons from Genetic Animal Models. Neuroscientist 2020; 28:20-40. [PMID: 33198566 DOI: 10.1177/1073858420972662] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The understanding of the functional and structural changes occurring in the cerebral cortex and basal ganglia in Huntington's disease (HD) has benefited considerably from the generation of genetic animal models. Most studies of synaptic alterations in HD models have focused on the striatum, but a more complete picture of synaptic dysfunction in the cortico-basal ganglia-cortical loop is emerging. Here, we provide a review and analysis of current developments in the study of synaptic alterations in these areas using HD rodent models. Recent evidence indicates that cortical maldevelopment plays a role in synaptic dysfunction along the corticostriatal pathway that may have its roots in the way mutant huntingtin interacts with synaptic proteins. Furthermore, a progressive disconnection in the corticostriatal pathway leads to abnormal function engaging extrasynaptic N-methyl-D-aspartate glutamate receptors that contribute to eventual cell degeneration. In addition, biphasic increases followed by decreases in glutamate and dopamine release in the striatum could explain contrasting symptomatology in early and late stages of the disease. Changes in striatal output regions also are beginning to be examined. Finally, we highlight some therapeutic avenues aimed at rescuing synaptic dysfunction.
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Affiliation(s)
- Carlos Cepeda
- IDDRC, Jane and Terry Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Michael S Levine
- IDDRC, Jane and Terry Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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Palomar-Garcia A, Camara E. SeSBAT: Single Subject Brain Analysis Toolbox. Application to Huntington's Disease as a Preliminary Study. Front Syst Neurosci 2020; 14:488652. [PMID: 33117135 PMCID: PMC7550747 DOI: 10.3389/fnsys.2020.488652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 08/21/2020] [Indexed: 12/02/2022] Open
Abstract
Magnetic resonance imaging (MRI) biomarkers require complex processing routines that are time-consuming and labor-intensive for clinical users. The Single Subject Brain Analysis Toolbox (SeSBAT) is a fully automated MATLAB toolbox with a graphical user interface (GUI) that offers standardized and optimized protocols for the pre-processing and analysis of anatomical MRI data at the single-subject level. In this study, the two-fold strategy provided by SeSBAT is illustrated through its application on a cohort of 42 patients with Huntington’s disease (HD), in pre-manifest and early manifest stages, as a suitable model of neurodegenerative processes. On the one hand, hypothesis-driven analysis can be used to extract biomarkers of neurodegeneration in specific brain regions of interest (ROI-based analysis). On the other hand, an exploratory voxel-based morphometry (VBM) approach can detect volume changes due to neurodegeneration throughout the whole brain (whole-brain analysis). That illustration reveals the potential of SeSBAT in providing potential prognostic biomarkers in neurodegenerative processes in clinics, which could be critical to overcoming the limitations of current qualitative evaluation strategies, and thus improve the diagnosis and monitoring of neurodegenerative disorders. Furthermore, the importance of the availability of tools for characterization at the single-subject level has been emphasized, as there is high interindividual variability in the pattern of neurodegeneration. Thus, tools like SeSBAT could pave the way towards more effective and personalized medicine.
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Affiliation(s)
- Alicia Palomar-Garcia
- Cognition and Brain Plasticity Unit, IDIBELL (Institut d'Investigació Biomèdica de Bellvitge), Barcelona, Spain
| | - Estela Camara
- Department of Cognition, Development and Educational Psychology, University of Barcelona, Barcelona, Spain
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Gatto RG, Weissmann C. Diffusion Tensor Imaging in Preclinical and Human Studies of Huntington's Disease: What Have we Learned so Far? Curr Med Imaging 2020; 15:521-542. [PMID: 32008561 DOI: 10.2174/1573405614666181115113400] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 10/23/2018] [Accepted: 10/26/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Huntington's Disease is an irreversible neurodegenerative disease characterized by the progressive deterioration of specific brain nerve cells. The current evaluation of cellular and physiological events in patients with HD relies on the development of transgenic animal models. To explore such events in vivo, diffusion tensor imaging has been developed to examine the early macro and microstructural changes in brain tissue. However, the gap in diffusion tensor imaging findings between animal models and clinical studies and the lack of microstructural confirmation by histological methods has questioned the validity of this method. OBJECTIVE This review explores white and grey matter ultrastructural changes associated to diffusion tensor imaging, as well as similarities and differences between preclinical and clinical Huntington's Disease studies. METHODS A comprehensive review of the literature using online-resources was performed (Pub- Med search). RESULTS Similar changes in fractional anisotropy as well as axial, radial and mean diffusivities were observed in white matter tracts across clinical and animal studies. However, comparative diffusion alterations in different grey matter structures were inconsistent between clinical and animal studies. CONCLUSION Diffusion tensor imaging can be related to specific structural anomalies in specific cellular populations. However, some differences between animal and clinical studies could derive from the contrasting neuroanatomy or connectivity across species. Such differences should be considered before generalizing preclinical results into the clinical practice. Moreover, current limitations of this technique to accurately represent complex multicellular events at the single micro scale are real. Future work applying complex diffusion models should be considered.
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Affiliation(s)
- Rodolfo Gabriel Gatto
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, United States
| | - Carina Weissmann
- Insituto de Fisiología Biologia Molecular y Neurociencias-IFIBYNE-CONICET, University of Buenos Aires, Buenos Aires, Argentina
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Franklin GL, Camargo CHF, Meira AT, Lima NSC, Teive HAG. The Role of the Cerebellum in Huntington's Disease: a Systematic Review. THE CEREBELLUM 2020; 20:254-265. [PMID: 33029762 DOI: 10.1007/s12311-020-01198-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/30/2020] [Indexed: 11/25/2022]
Abstract
Huntington's disease (HD) is a rare neurological disorder characterized by progressive motor, cognitive, and psychiatric disturbances. Although striatum degeneration might justify most of the motor symptoms, there is an emerging evidence of involvement of extra-striatal structures, such as the cerebellum. To elucidate the cerebellar involvement and its afferences with motor, psychiatric, and cognitive symptoms in HD. A systematic search in the literature was performed in MEDLINE, LILACS, and Google Scholar databases. The research was broadened to include the screening of reference lists of review articles for additional studies. Studies available in the English language, dating from 1993 through May 2020, were included. Clinical presentation of patients with HD may not be considered as the result of an isolated primary striatal dysfunction. There is evidence that cerebellar involvement is an early event in HD and may occur independently of striatal degeneration. Also, the loss of the compensation role of the cerebellum in HD may be an explanation for the clinical onset of HD. Although more studies are needed to elucidate this association, the current literature supports that the cerebellum may integrate the natural history of neurodegeneration in HD.
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Affiliation(s)
- Gustavo L Franklin
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Rua General Carneiro 1103/102, Centro, Curitiba, Paraná, Brazil.
| | - Carlos Henrique F Camargo
- Neurological Diseases Group, Graduate Program in Internal Medicine, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Alex T Meira
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Rua General Carneiro 1103/102, Centro, Curitiba, Paraná, Brazil
| | - Nayra S C Lima
- Vila Velha University, Vila Velha, Espírito Santo, Brazil
| | - Hélio A G Teive
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Rua General Carneiro 1103/102, Centro, Curitiba, Paraná, Brazil
- Neurological Diseases Group, Graduate Program in Internal Medicine, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil
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38
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Sipione S, Monyror J, Galleguillos D, Steinberg N, Kadam V. Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications. Front Neurosci 2020; 14:572965. [PMID: 33117120 PMCID: PMC7574889 DOI: 10.3389/fnins.2020.572965] [Citation(s) in RCA: 181] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 08/31/2020] [Indexed: 12/12/2022] Open
Abstract
Gangliosides are glycosphingolipids highly abundant in the nervous system, and carry most of the sialic acid residues in the brain. Gangliosides are enriched in cell membrane microdomains ("lipid rafts") and play important roles in the modulation of membrane proteins and ion channels, in cell signaling and in the communication among cells. The importance of gangliosides in the brain is highlighted by the fact that loss of function mutations in ganglioside biosynthetic enzymes result in severe neurodegenerative disorders, often characterized by very early or childhood onset. In addition, changes in the ganglioside profile (i.e., in the relative abundance of specific gangliosides) were reported in healthy aging and in common neurological conditions, including Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis and epilepsy. At least in HD, PD and in some forms of epilepsy, experimental evidence strongly suggests a potential role of gangliosides in disease pathogenesis and potential treatment. In this review, we will summarize ganglioside functions that are crucial to maintain brain health, we will review changes in ganglioside levels that occur in major neurological conditions and we will discuss their contribution to cellular dysfunctions and disease pathogenesis. Finally, we will review evidence of the beneficial roles exerted by gangliosides, GM1 in particular, in disease models and in clinical trials.
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Affiliation(s)
- Simonetta Sipione
- Department of Pharmacology, Faculty of Medicine and Dentistry, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
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Zhang C, Wu Q, Liu H, Cheng L, Hou Z, Mori S, Hua J, Ross CA, Zhang J, Nopoulos PC, Duan W. Abnormal Brain Development in Huntington' Disease Is Recapitulated in the zQ175 Knock-In Mouse Model. Cereb Cortex Commun 2020; 1:tgaa044. [PMID: 32984817 PMCID: PMC7501464 DOI: 10.1093/texcom/tgaa044] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 01/29/2023] Open
Abstract
Emerging cellular and molecular studies are providing compelling evidence that altered brain development contributes to the pathogenesis of Huntington's disease (HD). There has been lacking longitudinal system-level data obtained from in vivo HD models supporting this hypothesis. Our human MRI study in children and adolescents with HD indicates that striatal development differs between the HD and control groups, with initial hypertrophy and more rapid volume decline in HD group. In this study, we aimed to determine whether brain development recapitulates the human HD during the postnatal period. Longitudinal structural MRI scans were conducted in the heterozygous zQ175 HD mice and their littermate controls. We found that male zQ175 HD mice recapitulated the region-specific abnormal volume development in the striatum and globus pallidus, with early hypertrophy and then rapidly decline in the regional volume. In contrast, female zQ175 HD mice did not show significant difference in brain volume development with their littermate controls. This is the first longitudinal study of brain volume development at the system level in HD mice. Our results suggest that altered brain development may contribute to the HD pathogenesis. The potential effect of gene therapies targeting on neurodevelopmental event is worth to consider for HD therapeutic intervention.
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Affiliation(s)
- Chuangchuang Zhang
- Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Qian Wu
- Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Hongshuai Liu
- Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Liam Cheng
- Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Zhipeng Hou
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Susumu Mori
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jun Hua
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205, USA
| | - Christopher A Ross
- Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21285, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jiangyang Zhang
- Deaprtment of Radiology, New York University Grossman School of Medicine, New York City, NY 10016, USA
| | - Peggy C Nopoulos
- Departments of Psychiatry, Neurology, Pediatrics, University of Iowa Carver College of Medicine, Iowa city, IA 52242, USA
| | - Wenzhen Duan
- Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21285, USA
- Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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40
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Martín-Flores N, Pérez-Sisqués L, Creus-Muncunill J, Masana M, Ginés S, Alberch J, Pérez-Navarro E, Malagelada C. Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease. Cell Death Dis 2020; 11:569. [PMID: 32732871 PMCID: PMC7392897 DOI: 10.1038/s41419-020-02775-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/08/2020] [Accepted: 07/10/2020] [Indexed: 12/20/2022]
Abstract
RTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington's disease (HD) patients' putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. To explore this hypothesis, ectopic mhtt was over expressed in cultured rat primary neurons. Moreover, the protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Finally, striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor-learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.
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Affiliation(s)
- Núria Martín-Flores
- Department of Biomedicine, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain.
- Institut de Neurociències, University of Barcelona, 08036, Barcelona, Catalonia, Spain.
| | - Leticia Pérez-Sisqués
- Department of Biomedicine, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- Institut de Neurociències, University of Barcelona, 08036, Barcelona, Catalonia, Spain
| | - Jordi Creus-Muncunill
- Department of Biomedicine, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- Institut de Neurociències, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08036, Barcelona, Spain
| | - Mercè Masana
- Department of Biomedicine, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- Institut de Neurociències, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08036, Barcelona, Spain
| | - Sílvia Ginés
- Department of Biomedicine, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- Institut de Neurociències, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08036, Barcelona, Spain
| | - Jordi Alberch
- Department of Biomedicine, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- Institut de Neurociències, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08036, Barcelona, Spain
| | - Esther Pérez-Navarro
- Department of Biomedicine, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- Institut de Neurociències, University of Barcelona, 08036, Barcelona, Catalonia, Spain
- IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08036, Barcelona, Spain
| | - Cristina Malagelada
- Department of Biomedicine, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain.
- Institut de Neurociències, University of Barcelona, 08036, Barcelona, Catalonia, Spain.
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08036, Barcelona, Spain.
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Cheong RY, Gabery S, Petersén Å. The Role of Hypothalamic Pathology for Non-Motor Features of Huntington's Disease. J Huntingtons Dis 2020; 8:375-391. [PMID: 31594240 PMCID: PMC6839491 DOI: 10.3233/jhd-190372] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Huntington’s disease (HD) is a fatal genetic neurodegenerative disorder. It has mainly been considered a movement disorder with cognitive symptoms and these features have been associated with pathology of the striatum and cerebral cortex. Importantly, individuals with the mutant huntingtin gene suffer from a spectrum of non-motor features often decades before the motor disorder manifests. These symptoms and signs include a range of psychiatric symptoms, sleep problems and metabolic changes with weight loss particularly in later stages. A higher body mass index at diagnosis is associated with slower disease progression. The common psychiatric symptom of apathy progresses with the disease. The fact that non-motor features are present early in the disease and that they show an association to disease progression suggest that unravelling the underlying neurobiological mechanisms may uncover novel targets for early disease intervention and better symptomatic treatment. The hypothalamus and the limbic system are important brain regions that regulate emotion, social cognition, sleep and metabolism. A number of studies using neuroimaging, postmortem human tissue and genetic manipulation in animal models of the disease has collectively shown that the hypothalamus and the limbic system are affected in HD. These findings include the loss of neuropeptide-expressing neurons such as orexin (hypocretin), oxytocin, vasopressin, somatostatin and VIP, and increased levels of SIRT1 in distinct nuclei of the hypothalamus. This review provides a summary of the results obtained so far and highlights the potential importance of these changes for the understanding of non-motor features in HD.
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Affiliation(s)
- Rachel Y Cheong
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Sanaz Gabery
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Åsa Petersén
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
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42
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Khair Md AM, Kabrt DO J, Falchek Md S. Drug-Resistant Epilepsy in Children with Juvenile Huntington's Disease: A Challenging Case and Brief Review. Qatar Med J 2020; 2020:18. [PMID: 32699773 PMCID: PMC7359632 DOI: 10.5339/qmj.2020.18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 01/27/2020] [Indexed: 11/21/2022] Open
Abstract
Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder with a progressive decline in cognitive, motor, and psychological function. Chorea tends to be the most common associated movement disorder, although other variants of several abnormal movements are also seen. Adult-onset HD is the most common subtype. Juvenile Huntington's disease (JHD) accounts for 5%–10% of all HD cases and presents as a rapidly progressive disorder with a multitude of characteristics. We report on a 9-year-old male with JHD who presented with refractory epilepsy. His EEG findings, seizure type, and antiepileptic drug usage are discussed with a brief review of the currently available relevant literature. The currently reported case sheds light on antiepileptic drugs that proved effective in our patient and the importance of screening for JHD when a child presents with seizures that are difficult to control.
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Affiliation(s)
- Abdulhafeez M Khair Md
- Pediatric Neurology Fellow. Ai.I. Dupont Hospital for Children - Thomas Jefferson University. 1600 Rockland Rd, Wilington DE 19809, United States
| | - Jessica Kabrt DO
- Osteopathic medical student, Rowan University. 42 e Laurel Rd, Stratford NJ 08084, United States
| | - Stephen Falchek Md
- Division chief of neurology- A.I Dupont Hospital for Children Wilmington DE. Assistant professor-Thomas Jefferson University-Philadelphia PA, United States
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43
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Júlio F, Ribeiro MJ, Morgadinho A, Sousa M, van Asselen M, Simões MR, Castelo-Branco M, Januário C. Cognition, function and awareness of disease impact in early Parkinson's and Huntington's disease. Disabil Rehabil 2020; 44:921-939. [PMID: 32620060 DOI: 10.1080/09638288.2020.1783001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Purpose: Patients with Parkinson's and Huntington's Disease (PD and HD) present impairments in cognitively challenging everyday activities. This study contrasts these two basal ganglia disorders on the ability to perform daily life- like tasks and their level of awareness regarding the disease impact on function.Methods: 19 controls, 10 early-onset PD, 20 early stage PD, and 15 early manifest HD patients were compared in the "EcoKitchen," a virtual reality task with increasing executive load, the "Behavioural Assessment of Dysexecutive Syndrome battery - BADS," and "The Adults and Older Adults Functional Assessment Inventory - IAFAI," a self-report functional questionnaire. The EcoKitchen clinical correlates were investigated.Results: All clinical groups presented slower EcoKitchen performance than controls, however, only HD patients showed decreased accuracy. HD and PD patients exhibited reduced BADS scores compared to the other study participants. Importantly, on the IAFAI, PD patients signalled more physically related incapacities and HD patients indicated more cognitively related incapacities. Accordingly, the EcoKitchen performance was significantly associated with PD motor symptom severity.Conclusions: Our findings suggest differential disease impact on cognition and function across PD and HD patients, with preserved awareness regarding disease- related functional sequelae. These observations have important implications for clinical management, research and rehabilitation.Implications for rehabilitationPatients with early stage Parkinson's and Huntington's disease have diagnosis-specific impairments in the performance of executively demanding everyday activities and, yet, show preserved awareness about the disease impact on their daily life.An active involvement of patients in the rehabilitation process should be encouraged, as their appraisal of the disease effects can help on practical decisions about meaningful targets for intervention, vocational choices, quality-of-life issues and/or specific everyday skills to boost.The EcoKitchen, a non-immersive virtual reality task, can detect and quantify early deficits in everyday-like tasks and is therefore a valuable tool for assessing the effects of rehabilitation strategies on the functional cognition of these patients.Rehabilitation efforts in the mild stages of Parkinson's and Huntington's disease should be aware of greater time needs from the patients in the performance of daily life tasks, target executive skills, and give a more prominent role to patients in symptoms report and management.
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Affiliation(s)
- Filipa Júlio
- University of Coimbra, Faculty of Psychology and Education Sciences, Coimbra, Portugal.,University of Coimbra, Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Coimbra, Portugal
| | - Maria J Ribeiro
- University of Coimbra, Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Coimbra, Portugal
| | | | - Mário Sousa
- Coimbra University Hospital, Coimbra, Portugal
| | - Marieke van Asselen
- University of Coimbra, Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Coimbra, Portugal
| | - Mário R Simões
- University of Coimbra, Faculty of Psychology and Education Sciences, Coimbra, Portugal.,University of Coimbra, Faculty of Psychology and Education Sciences, Center for Research in Neuropsychology and Cognitive Behavioural Intervention (CINEICC), Coimbra, Portugal
| | - Miguel Castelo-Branco
- University of Coimbra, Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Coimbra, Portugal.,University of Coimbra, Institute of Nuclear Sciences Applied to Health (ICNAS), Coimbra, Portugal.,University of Coimbra, Faculty of Medicine, Coimbra, Portugal
| | - Cristina Januário
- University of Coimbra, Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Coimbra, Portugal.,Coimbra University Hospital, Coimbra, Portugal.,University of Coimbra, Faculty of Medicine, Coimbra, Portugal
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44
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Moreno-Delgado D, Puigdellívol M, Moreno E, Rodríguez-Ruiz M, Botta J, Gasperini P, Chiarlone A, Howell LA, Scarselli M, Casadó V, Cortés A, Ferré S, Guzmán M, Lluís C, Alberch J, Canela EI, Ginés S, McCormick PJ. Modulation of dopamine D 1 receptors via histamine H 3 receptors is a novel therapeutic target for Huntington's disease. eLife 2020; 9:51093. [PMID: 32513388 PMCID: PMC7282811 DOI: 10.7554/elife.51093] [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: 08/14/2019] [Accepted: 05/26/2020] [Indexed: 01/11/2023] Open
Abstract
Early Huntington's disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H3R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D1R - H3R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.
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Affiliation(s)
- David Moreno-Delgado
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
| | - Mar Puigdellívol
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.,Department of Biomedical Science, Faculty of Medicine, University of Barcelona, Institut of Neuroscience, Barcelona, Spain.,Institut d´Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
| | - Estefanía Moreno
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
| | - Mar Rodríguez-Ruiz
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
| | - Joaquín Botta
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.,School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
| | - Paola Gasperini
- School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
| | - Anna Chiarlone
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.,Department of Biochemistry and Molecular Biology I, School of Biology, Instituto Universitario de Investigación Neuroquímica, and Instituto Ramón y Cajal de Investigación Sanitaria, Complutense University of Madrid, Madrid, Spain
| | - Lesley A Howell
- School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom
| | - Marco Scarselli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Vicent Casadó
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
| | - Antoni Cortés
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
| | - Sergi Ferré
- National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, United States
| | - Manuel Guzmán
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.,Department of Biochemistry and Molecular Biology I, School of Biology, Instituto Universitario de Investigación Neuroquímica, and Instituto Ramón y Cajal de Investigación Sanitaria, Complutense University of Madrid, Madrid, Spain
| | - Carmen Lluís
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
| | - Jordi Alberch
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.,Department of Biomedical Science, Faculty of Medicine, University of Barcelona, Institut of Neuroscience, Barcelona, Spain.,Institut d´Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Enric I Canela
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
| | - Silvia Ginés
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.,Department of Biomedical Science, Faculty of Medicine, University of Barcelona, Institut of Neuroscience, Barcelona, Spain.,Institut d´Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Peter J McCormick
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.,School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.,William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
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45
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Chakroborty S, Manfredsson FP, Dec AM, Campbell PW, Stutzmann GE, Beaumont V, West AR. Phosphodiesterase 9A Inhibition Facilitates Corticostriatal Transmission in Wild-Type and Transgenic Rats That Model Huntington's Disease. Front Neurosci 2020; 14:466. [PMID: 32581668 PMCID: PMC7283904 DOI: 10.3389/fnins.2020.00466] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 04/15/2020] [Indexed: 12/18/2022] Open
Abstract
Huntington's disease (HD) results from abnormal expansion in CAG trinucleotide repeats within the HD gene, a mutation which leads to degeneration of striatal medium-sized spiny neurons (MSNs), deficits in corticostriatal transmission, and loss of motor control. Recent studies also indicate that metabolism of cyclic nucleotides by phosphodiesterases (PDEs) is dysregulated in striatal networks in a manner linked to deficits in corticostriatal transmission. The current study assessed cortically-evoked firing in electrophysiologically-identified MSNs and fast-spiking interneurons (FSIs) in aged (9-11 months old) wild-type (WT) and BACHD transgenic rats (TG5) treated with vehicle or the selective PDE9A inhibitor PF-04447943. WT and TG5 rats were anesthetized with urethane and single-unit activity was isolated during low frequency electrical stimulation of the ipsilateral motor cortex. Compared to WT controls, MSNs recorded in TG5 animals exhibited decreased spike probability during cortical stimulation delivered at low to moderate stimulation intensities. Moreover, large increases in onset latency of cortically-evoked spikes and decreases in spike probability were observed in FSIs recorded in TG5 animals. Acute systemic administration of the PDE9A inhibitor PF-04447943 significantly decreased the onset latency of cortically-evoked spikes in MSNs recorded in WT and TG5 rats. PDE9A inhibition also increased the proportion of MSNs responding to cortical stimulation and reversed deficits in spike probability observed in TG5 rats. As PDE9A is a cGMP specific enzyme, drugs such as PF-04447943 which act to facilitate striatal cGMP signaling and glutamatergic corticostriatal transmission could be useful therapeutic agents for restoring striatal function and alleviating motor and cognitive symptoms associated with HD.
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Affiliation(s)
- Shreaya Chakroborty
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Fredric P Manfredsson
- Parkinson's Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, United States
| | - Alexander M Dec
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Peter W Campbell
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Grace E Stutzmann
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Vahri Beaumont
- CHDI Management/CHDI Foundation, Los Angeles, CA, United States
| | - Anthony R West
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
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Lamirault C, Nguyen HP, Doyère V, El Massioui N. Age-related alteration of emotional regulation in the BACHD rat model of Huntington disease. GENES, BRAIN, AND BEHAVIOR 2020; 19:e12633. [PMID: 31883197 DOI: 10.1111/gbb.12633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/29/2019] [Accepted: 12/23/2019] [Indexed: 06/10/2023]
Abstract
Huntington's disease (HD) is a genetic neurodegenerative disorder, caused by an expanded CAG repeat in the gene encoding the huntingtin protein. At the premanifest phase, before motor symptoms occur, psychiatric and emotional disorders are observed with high prevalence in HD patients. Agitation, anxiety and irritability are often described but also depression and/or apathy, associated with a lack of emotional control. The aim of the present study was to better circumscribe and understand the emotional symptoms and assess their evolution according to the progression of the disease using a transgenic HD model, BACHD rats, at the age of 4, 12 and 18 months. To achieve this goal, we confronted animals to two types of tests: first, tests assessing anxiety like the light/dark box and the conflict test, which are situations that did not involve an obvious threat and tests assessing the reactivity to a present threat using confrontation with an unknown conspecific (social behavior test) or with an aversive stimulus (fear conditioning test). In all animals, results show an age-dependent anxiety-like behavior, particularly marked in situation requiring passive responses (light/dark box and fear conditioning tests). BACHD rats exhibited a more profound alteration than WT animals in these tests from an early stage of the disease whereas, in tasks requiring some kind of motivation (for food or for social contacts), only old BACHD rats showed high anxiety-like behavior compared to WT, may be partly due to the other symptoms' occurrence at this stage: locomotor difficulties and/or apathy.
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Affiliation(s)
- Charlotte Lamirault
- Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, Gif-sur-Yvette, France
| | - Huu Phuc Nguyen
- Department of Human Genetics, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany
| | - Valérie Doyère
- Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, Gif-sur-Yvette, France
| | - Nicole El Massioui
- Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, Gif-sur-Yvette, France
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Protein changes in synaptosomes of Huntington's disease knock-in mice are dependent on age and brain region. Neurobiol Dis 2020; 141:104950. [PMID: 32439598 DOI: 10.1016/j.nbd.2020.104950] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 03/19/2020] [Accepted: 05/16/2020] [Indexed: 12/15/2022] Open
Abstract
Molecular changes at synapses are thought to underly the deficits in motor and cognitive dysfunction seen in Huntington's disease (HD). Previously we showed in synaptosome preparations age dependent changes in levels of selected proteins examined by western blot assay in the striatum of Q140/Q140 HD mice. To assess if CAG repeat length influenced protein changes at the synapse, we examined synaptosomes from 6-month old heterozygote HD mice with CAG repeat lengths ranging from 50 to 175. Analysis of 19 selected proteins showed that increasing CAG repeat length in huntingtin (HTT) increased the number of affected proteins in HD striatal synaptosomes. Moreover, SDS-soluble total HTT (WT plus mutant HTT) and pThr3 HTT were reduced with increasing CAG repeat length, and there was no pSer421 mutant HTT detected in any HD mice. A LC-MS/MS and bioinfomatics study of synaptosomes from 2 and 6-month old striatum and cortex of Q140/Q7 HD mice showed enrichment of synaptic proteins and an influence of age, gender and brain region on the number of protein changes. HD striatum at 6 months had the most protein changes that included many HTT protein interactors, followed by 2-month old HD striatum, 2-month old HD cortex and 6-month HD cortex. SDS-insoluble mutant HTT was detected in HD striatal synaptosomes consistent with the presence of aggregates. Proteins changed in cortex differed from those in striatum. Pathways affected in HD striatal synaptosomes that were not identified in whole striatal lysates of the same HD mouse model included axon guidance, focal adhesion, neurotrophin signaling, regulation of actin cytoskeleton, endocytosis, and synaptic vesicle cycle. Results suggest that synaptosomes prepared from HD mice are highly informative for monitoring protein changes at the synapse and may be preferred for assessing the effects of experimental therapies on synaptic function in HD.
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Furlong LS, Jakabek D, Power BD, Owens-Walton C, Wilkes FA, Walterfang M, Velakoulis D, Egan G, Looi JC, Georgiou-Karistianis N. Morphometric in vivo evidence of thalamic atrophy correlated with cognitive and motor dysfunction in Huntington's disease: The IMAGE-HD study. Psychiatry Res Neuroimaging 2020; 298:111048. [PMID: 32120305 DOI: 10.1016/j.pscychresns.2020.111048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 02/09/2020] [Accepted: 02/14/2020] [Indexed: 01/18/2023]
Abstract
In Huntington's disease (HD), neurodegeneration causes progressive atrophy to the striatum, cortical areas, and white matter tracts - components of corticostriatal circuitry. Such processes may affect the thalamus, a key circuit node. We investigated whether differences in dorsal thalamic morphology were detectable in HD, and whether thalamic atrophy was associated with neurocognitive, neuropsychiatric and motor dysfunction. Magnetic resonance imaging scans and clinical outcome measures were obtained from 34 presymptomatic HD (pre-HD), 29 early symptomatic HD (symp-HD), and 26 healthy control individuals who participated in the IMAGE-HD study. Manual region of interest (ROI) segmentation was conducted to measure dorsal thalamic volume, and thalamic ROI underwent shape analysis using the spherical harmonic point distribution method. The symp-HD group had significant thalamic volumetric reduction and global shape deflation, indicative of atrophy, compared to pre-HD and control groups. Thalamic atrophy significantly predicted neurocognitive and motor dysfunction within the symp-HD group only. Thalamic morphology differentiates symp-HD from pre-HD and healthy individuals. Thalamic changes may be one of the structural bases (endomorphotypes), of the endophenotypic neurocognitive and motor manifestations of disease. Future research should continue to investigate the thalamus as a potential in vivo biomarker of disease progression in HD.
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Affiliation(s)
- Lisa S Furlong
- Research Centre for the Neurosciences of Ageing, Academic Unit of Psychiatry and Addiction Medicine, School of Clinical Medicine, Australian National University Medical School, Canberra, Australia; John Curtin School of Medical Research, Australian National University, Canberra, Australia.
| | - David Jakabek
- Graduate School of Medicine, University of Wollongong, Wollongong, Australia
| | - Brian D Power
- School of Medicine Fremantle, The University of Notre Dame Australia, Fremantle, Australia; Clinical Research Centre, North Metropolitan Health Service - Mental Health, WA, Australia
| | - Conor Owens-Walton
- Research Centre for the Neurosciences of Ageing, Academic Unit of Psychiatry and Addiction Medicine, School of Clinical Medicine, Australian National University Medical School, Canberra, Australia
| | - Fiona A Wilkes
- Research Centre for the Neurosciences of Ageing, Academic Unit of Psychiatry and Addiction Medicine, School of Clinical Medicine, Australian National University Medical School, Canberra, Australia
| | - Mark Walterfang
- Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne Neuropsychiatry Centre, and University of Melbourne, Melbourne, Australia
| | - Dennis Velakoulis
- Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne Neuropsychiatry Centre, and University of Melbourne, Melbourne, Australia
| | - Gary Egan
- School of Psychological Sciences and The Turner Institute for Brain and Mental Health Monash University, Clayton, Australia; Monash Biomedical Imaging, Monash University, Clayton, Australia; Life Sciences Computation Centre, Victorian Life Sciences Computation Initiative, Melbourne, Australia
| | - Jeffrey Cl Looi
- Research Centre for the Neurosciences of Ageing, Academic Unit of Psychiatry and Addiction Medicine, School of Clinical Medicine, Australian National University Medical School, Canberra, Australia; Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne Neuropsychiatry Centre, and University of Melbourne, Melbourne, Australia
| | - Nellie Georgiou-Karistianis
- School of Psychological Sciences and The Turner Institute for Brain and Mental Health Monash University, Clayton, Australia
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Structural Variant in Mitochondrial-Associated Gene (MRPL3) Induces Adult-Onset Neurodegeneration with Memory Impairment in the Mouse. J Neurosci 2020; 40:4576-4585. [PMID: 32341096 DOI: 10.1523/jneurosci.0013-20.2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 12/31/2022] Open
Abstract
An impediment to the development of effective therapies for neurodegenerative disease is that available animal models do not reproduce important clinical features such as adult-onset and stereotypical patterns of progression. Using in vivo magnetic resonance imaging and behavioral testing to study male and female decrepit mice, we found a stereotypical neuroanatomical pattern of progression of the lesion along the limbic system network and an associated memory impairment. Using structural variant analysis, we identified an intronic mutation in a mitochondrial-associated gene (Mrpl3) that is responsible for the decrepit phenotype. While the function of this gene is unknown, embryonic lethality in Mrpl3 knock-out mice suggests it is critical for early development. The observation that a mutation linked to energy metabolism precipitates a pattern of neurodegeneration via cell death across disparate but linked brain regions may explain how stereotyped patterns of neurodegeneration arise in humans or define a not yet identified human disease.SIGNIFICANCE STATEMENT The development of novel therapies for adult-onset neurodegenerative disease has been impeded by the limitations of available animal models in reproducing many of the clinical features. Here, we present a novel spontaneous mutation in a mitochondrial-associated gene in a mouse (termed decrepit) that results in adult-onset neurodegeneration with a stereotypical neuroanatomical pattern of progression and an associated memory impairment. The decrepit mouse model may represent a heretofore undiagnosed human disease and could serve as a new animal model to study neurodegenerative disease.
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Savage JC, St-Pierre MK, Carrier M, El Hajj H, Novak SW, Sanchez MG, Cicchetti F, Tremblay MÈ. Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington's disease pathology. J Neuroinflammation 2020; 17:98. [PMID: 32241286 PMCID: PMC7118932 DOI: 10.1186/s12974-020-01782-9] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 03/20/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder that affects cognitive and motor abilities by primarily targeting the striatum and cerebral cortex. HD is caused by a mutation elongating the CAG repeats within the Huntingtin gene, resulting in HTT protein misfolding. Although the genetic cause of HD has been established, the specific susceptibility of neurons within various brain structures has remained elusive. Microglia, which are the brain's resident macrophages, have emerged as important players in neurodegeneration. Nevertheless, few studies have examined their implication in HD. METHODS To provide novel insights, we investigated the maturation and dysfunction of striatal microglia using the R6/2 mouse model of HD. This transgenic model, which presents with 120+/-5 CAG repeats, displays progressive motor deficits beginning at 6 weeks of age, with full incapacitation by 13 weeks. We studied microglial morphology, phagocytic capacity, and synaptic contacts in the striatum of R6/2 versus wild-type (WT) littermates at 3, 10, and 13 weeks of age, using a combination of light and transmission electron microscopy. We also reconstructed dendrites and determined synaptic density within the striatum of R6/2 and WT littermates, at nanoscale resolution using focused ion beam scanning electron microscopy. RESULTS At 3 weeks of age, prior to any known motor deficits, microglia in R6/2 animals displayed a more mature morphological phenotype than WT animals. Microglia from R6/2 mice across all ages also demonstrated increased phagocytosis, as revealed by light microscopy and transmission electron microscopy. Furthermore, microglial processes from 10-week-old R6/2 mice made fewer contacts with synaptic structures than microglial processes in 3-week-old R6/2 mice and age-matched WT littermates. Synaptic density was not affected by genotype at 3 weeks of age but increased with maturation in WT mice. The location of synapses was lastly modified in R6/2 mice compared with WT controls, from targeting dendritic spines to dendritic trunks at both 3 and 10 weeks of age. CONCLUSIONS These findings suggest that microglia may play an intimate role in synaptic alteration and loss during HD pathogenesis.
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Affiliation(s)
- Julie C Savage
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, 2705, Boulevard Laurier, T2-50, Québec, QC, G1V 4G2, Canada.
| | - Marie-Kim St-Pierre
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, 2705, Boulevard Laurier, T2-50, Québec, QC, G1V 4G2, Canada
| | - Micaël Carrier
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, 2705, Boulevard Laurier, T2-50, Québec, QC, G1V 4G2, Canada
| | - Hassan El Hajj
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, 2705, Boulevard Laurier, T2-50, Québec, QC, G1V 4G2, Canada
| | - Sammy Weiser Novak
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, 2705, Boulevard Laurier, T2-50, Québec, QC, G1V 4G2, Canada
- Waitt Advanced Biophotonics Core, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Maria Gabriela Sanchez
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, 2705, Boulevard Laurier, T2-50, Québec, QC, G1V 4G2, Canada
| | - Francesca Cicchetti
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, 2705, Boulevard Laurier, T2-50, Québec, QC, G1V 4G2, Canada
- Département de psychiatrie et neurosciences, Faculté de médecine, Université Laval, Québec, QC, Canada
| | - Marie-Ève Tremblay
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, 2705, Boulevard Laurier, T2-50, Québec, QC, G1V 4G2, Canada.
- Département de médecine moléculaire, Faculté de médecine, Université Laval, Québec, QC, Canada.
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
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