Transcriptional and electrophysiological aberrations in an induced pluripotent stem cell-derived model of spinocerebellar ataxia type 7

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease that is characterised by ataxia and visual loss. It results from a degeneration of cerebellar Purkinje neurons and retinal photoreceptors caused by a polyglutamine repeat expansion in the ATXN7 gene, a component of the STAGA transcription co-activator complex. As with many neurodegenerative diseases, studies of pathogenesis have been hindered by a lack of disease-relevant models. To this end, we have generated the first induced pluripotent stem cells (iPSCs) from South African SCA7 patients, where the disease occurs at an unusually high frequency as a result of a founder effect. These iPSCs were capable of differentiation into neural and retinal cells, and showed evidence of a transcriptional phenotype affecting components of STAGA (ATXN7 and KAT2A) and the heat shock protein pathway (DNAJA1 and HSP70). Functionally, SCA7 iPSC-derived neurons exhibited more negative resting membrane potentials and increased input resistance compared to controls, suggesting reduced excitability in response to synaptic input. These results provide the first evidence of a disease phenotype in SCA7 iPSC-derived cells, establishing a valuable model for the study of neurodegenerative diseases and the development of population-specific therapies.