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. 2023 Aug;38(8):1428-1442.
doi: 10.1002/mds.29446. Epub 2023 Jun 6.

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

Ronald A M Buijsen  1 , Michel Hu  1   2 , Maria Sáez-González  1 , Sofia Notopoulou  3 , Eleni Mina  1 , Winette Koning  1 , Sarah L Gardiner  1   2 , Linda M van der Graaf  1 , Elena Daoutsali  1 , Barry A Pepers  1 , Hailiang Mei  4 , Vera van Dis  5   6 , Jean-Philippe Frimat  1   2 , Arn M J M van den Maagdenberg  1   2 , Spyros Petrakis  3 , Willeke M C van Roon-Mom  1
Affiliations

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

Ronald A M Buijsen et al. Mov Disord. 2023 Aug.

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

Keywords: MEA; RNA sequencing; bioenergetics; disease modelling; electrophysiology; human induced pluripotent stem cells; neurodegeneration; neuronal aggregates; neuronal morphology; spinocerebellar ataxia type 1.

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