دورية أكاديمية
Spinocerebellar Ataxia Type 1 Characteristics in Patient-Derived Fibroblast and iPSC-Derived Neuronal Cultures.
العنوان: | Spinocerebellar Ataxia Type 1 Characteristics in Patient-Derived Fibroblast and iPSC-Derived Neuronal Cultures. |
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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 |
تدمد: | 1531-8257 |
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DOI: | 10.1002/mds.29446 |