Dysregulation of alternative splicing is a transcriptomic feature of patient-derived fibroblasts from CAG repeat expansion spinocerebellar ataxias.

The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of rare dominantly inherited neurodegenerative diseases characterized by progressive ataxia. The most common mutation seen across the SCAs is a CAG repeat expansion, causative for SCA1, 2, 3, 6, 7, 12 and 17. We recently identified dysregulation of alternative splicing as a novel, presymptomatic transcriptomic hallmark in mouse models of SCAs 1, 3 and 7. In order to understand if dysregulation of alternative splicing is a transcriptomic feature of patient-derived cell models of CAG SCAs, we performed RNA sequencing and transcriptomic analysis in patient-derived fibroblast cell lines of SCAs 1, 3 and 7. We identified widespread and robust dysregulation of alternative splicing across all CAG expansion SCA lines investigated, with disease relevant pathways affected, such as microtubule-based processes, transcriptional regulation, and DNA damage and repair. Novel disease-relevant alternative splicing events were validated across patient-derived fibroblast lines from multiple CAG SCAs and CAG containing reporter cell lines. Together this study demonstrates that dysregulation of alternative splicing represents a novel and shared pathogenic process in CAG expansion SCA1, 3 and 7 and can potentially be used as a biomarker across patient models of this group of devastating neurodegenerative diseases.