Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells

PLoS One. 2021 Feb 24;16(2):e0247434. doi: 10.1371/journal.pone.0247434. eCollection 2021.

Abstract

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the ATXN7 gene. Patients with this disease suffer from a degeneration of their cerebellar Purkinje neurons and retinal photoreceptors that result in a progressive ataxia and loss of vision. As with many neurodegenerative diseases, studies of pathogenesis have been hindered by a lack of disease-relevant models. To this end, we have generated induced pluripotent stem cells (iPSCs) from a cohort of SCA7 patients in South Africa. First, we differentiated the SCA7 affected iPSCs into neurons which showed evidence of a transcriptional phenotype affecting components of STAGA (ATXN7 and KAT2A) and the heat shock protein pathway (DNAJA1 and HSP70). We then performed electrophysiology on the SCA7 iPSC-derived neurons and found that these cells show features of functional aberrations. Lastly, we were able to differentiate the SCA7 iPSCs into retinal photoreceptors that also showed similar transcriptional aberrations to the SCA7 neurons. Our findings give technical insights on how iPSC-derived neurons and photoreceptors can be derived from SCA7 patients and demonstrate that these cells express molecular and electrophysiological differences that may be indicative of impaired neuronal health. We hope that these findings will contribute towards the ongoing efforts to establish the cell-derived models of neurodegenerative diseases that are needed to develop patient-specific treatments.

Grant support

Funding for this work was provided by Ataxia UK, Commonwealth Scholarship Commission (UK), John Fell OUP Fund, National Research Foundation (South Africa), National Research Foundation (South Africa, Competitive Programme for Rated Researchers CPR20110624000019696), Medical Research Council (South Africa), Harry Crossley Foundation, Deutscher Akademischer Austausch Dienst, University of Cape Town Research Council, Wellcome Trust, Parkinson’s Disease UK, Medical Research Council UK, Blue Brain Project, and the James Martin 21st Century School. Electrophysiology equipment was provided by the École Polytechnique Fédérale de Lausanne, Switzerland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.