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Spinocerebellar Ataxia Type 1 Characteristics in Patient-Derived Fibroblast and iPSC-Derived Neuronal Cultures.

التفاصيل البيبلوغرافية
العنوان: Spinocerebellar Ataxia Type 1 Characteristics in Patient-Derived Fibroblast and iPSC-Derived Neuronal Cultures.
المؤلفون: Buijsen RAM; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., Hu M; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands.; Department of Neurology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., Sáez-González M; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., Notopoulou S; Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece., Mina E; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., Koning W; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., Gardiner SL; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands.; Department of Neurology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., van der Graaf LM; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., Daoutsali E; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., Pepers BA; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., Mei H; Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., van Dis V; Department of Pathology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands.; Department of Pathology, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands., Frimat JP; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands.; Department of Neurology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., van den Maagdenberg AMJM; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands.; Department of Neurology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands., Petrakis S; Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece., van Roon-Mom WMC; Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands.
المصدر: Movement disorders : official journal of the Movement Disorder Society [Mov Disord] 2023 Aug; Vol. 38 (8), pp. 1428-1442. Date of Electronic Publication: 2023 Jun 06.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8610688 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1531-8257 (Electronic) Linking ISSN: 08853185 NLM ISO Abbreviation: Mov Disord Subsets: MEDLINE
أسماء مطبوعة: Publication: <2001->: New York, NY : Wiley-Liss
Original Publication: [New York, N.Y.] : Raven Press, [c1986-
مواضيع طبية MeSH: Induced Pluripotent Stem Cells* , Spinocerebellar Ataxias*/metabolism, Mice ; Animals ; Ataxins/metabolism ; Protein Aggregates ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/genetics ; Mice, Transgenic ; Purkinje Cells/metabolism ; Purkinje Cells/pathology ; Fibroblasts/metabolism
مستخلص: Background: Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by a polyglutamine expansion in the ataxin-1 protein resulting in neuropathology including mutant ataxin-1 protein aggregation, aberrant neurodevelopment, and mitochondrial dysfunction.
Objectives: Identify SCA1-relevant phenotypes in patient-specific fibroblasts and SCA1 induced pluripotent stem cells (iPSCs) neuronal cultures.
Methods: SCA1 iPSCs were generated and differentiated into neuronal cultures. Protein aggregation and neuronal morphology were evaluated using fluorescent microscopy. Mitochondrial respiration was measured using the Seahorse Analyzer. The multi-electrode array (MEA) was used to identify network activity. Finally, gene expression changes were studied using RNA-seq to identify disease-specific mechanisms.
Results: Bioenergetics deficits in patient-derived fibroblasts and SCA1 neuronal cultures showed altered oxygen consumption rate, suggesting involvement of mitochondrial dysfunction in SCA1. In SCA1 hiPSC-derived neuronal cells, nuclear and cytoplasmic aggregates were identified similar in localization as aggregates in SCA1 postmortem brain tissue. SCA1 hiPSC-derived neuronal cells showed reduced dendrite length and number of branching points while MEA recordings identified delayed development in network activity in SCA1 hiPSC-derived neuronal cells. Transcriptome analysis identified 1050 differentially expressed genes in SCA1 hiPSC-derived neuronal cells associated with synapse organization and neuron projection guidance, where a subgroup of 151 genes was highly associated with SCA1 phenotypes and linked to SCA1 relevant signaling pathways.
Conclusions: Patient-derived cells recapitulate key pathological features of SCA1 pathogenesis providing a valuable tool for the identification of novel disease-specific processes. This model can be used for high throughput screenings to identify compounds, which may prevent or rescue neurodegeneration in this devastating disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
(© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
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فهرسة مساهمة: Keywords: MEA; RNA sequencing; bioenergetics; disease modelling; electrophysiology; human induced pluripotent stem cells; neurodegeneration; neuronal aggregates; neuronal morphology; spinocerebellar ataxia type 1
المشرفين على المادة: 0 (Ataxins)
0 (Protein Aggregates)
0 (Nerve Tissue Proteins)
0 (Nuclear Proteins)
تواريخ الأحداث: Date Created: 20230606 Date Completed: 20230814 Latest Revision: 20230818
رمز التحديث: 20230819
DOI: 10.1002/mds.29446
PMID: 37278528
قاعدة البيانات: MEDLINE
الوصف
تدمد:1531-8257
DOI:10.1002/mds.29446