Cardiovascular exercise drives neuroprotection in Spinocerebellar Ataxia 1 via rescue of abherrant splicing

Objective: Spinocerebellar Ataxia 1 (SCA1) is a fatal hereditary neurodegenerative disorder with no approved therapies, and gene-targeting strategies have thus far failed in clinical trials. Exercise remains the only intervention shown to provide clinical benefit in patients with spinocerebellar ataxias, yet the underlying mechanisms remain poorly understood. Results: Unrestricted exercise rescued motor ataxia in SCA1 mice but not degeneration in this model at the ages in this study. Transcriptional profiling of cerebellar tissue did separate WT sedentary and exercise mice by differential gene expression, but in SCA1 mice the most pronounced changes occurred at the level of RNA splicing, particularly in ion channel modules. Exercise led to a significant rescue of splicing events in SCA1 mice, with minimal impact on gene expression changes. Further, both exercised SCA1 and wild-type mice exhibited splicing patterns more similar to each other than their sedentary counterparts. Interpretation: Together with emerging evidence in other SCAs, our findings confirm aberrant splicing as a central driver of spinocerebellar ataxia (SCA) pathophysiology and identify splicing-regulated networks as actionable therapeutic targets. The observed benefits in SCA1 mice suggest that pharmacologic activation of ion channels may be a viable strategy to mimic exercise for disease modification across SCAs and related neurodegenerative disorders.