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

Ronald A.M. Buijsen*, Michel Hu, Maria Sáez-González, Sofia Notopoulou, Eleni Mina, Winette Koning, Sarah L. Gardiner, Linda M. van der Graaf, Elena Daoutsali, Barry A. Pepers, Hailiang Mei, Vera van Dis, Jean Philippe Frimat, Arn M.J.M. van den Maagdenberg, Spyros Petrakis, Willeke M.C. van Roon-Mom

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)1428-1442
Number of pages15
JournalMovement Disorders
Volume38
Issue number8
Early online date6 Jun 2023
DOIs
Publication statusPublished - Aug 2023

Bibliographical note

Funding Information:
This research is funded by Hersenstichting (Dutch Brain Foundation) projects HA2016‐02‐02 (W.M.C.v.R.‐M.), DR‐2018‐00253 (R.A.M.B.), and ZonMw PTO2 project 446002002 (R.A.M.B and W.M.C.v.R.‐M). This work was supported by the Netherlands Organ‐on‐Chip Initiative, an NWO Gravitation project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of the Netherlands (A.M.J.M.v.d.M. and J.P.F.). Funding agencies:

Publisher Copyright:
© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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