Title : Aerobic exercise enhances motor and cognitive performance and restores aberrant splicing in SCA1 mice
Abstract:
Spinocerebellar Ataxias (SCAs) are progressive neurodegenerative disorders that primarily affect the cerebellum, leading to motor dysfunction, cognitive decline, and premature death. A hallmark of SCA pathology is the dysregulation of Purkinje cell firing, which occurs prior to cell degeneration. This irregularity is thought to be partially driven by alternative splicing of exons in genes encoding calcium channels. Despite these insights, there are currently no effective therapies for any form of SCA. Although challenging for this patient population, emerging evidence from human studies suggests that regular aerobic exercise may slow the progression of neurodegenerative diseases. However, the underlying mechanisms remain poorly understood. In this study, we used a well-established knock-in mouse model of SCA1 to investigate the effects of consistent voluntary aerobic exercise. Exercised mice showed significant improvements in motor coordination, balance, and cognitive performance compared to sedentary controls after 12 weeks of exercise. Bulk RNA sequencing of the cerebellum revealed robust transcriptional changes in response to exercise. Notably, we identified exercise-associated alterations in BK channel splicing, including in Trpc3 and Anks1b, although exercise did not rescue splicing changes in these genes. In contrast, we observed a significant rescue of Kcnma1 splicing to wild-type levels, despite no detectable differences in cerebellar degeneration at this stage. These findings suggest that aerobic exercise can modulate RNA splicing in SCA1 prior to overt cerebellar degeneration. These results can not only help us better understand the impact of aerobic exercise on neurodegeneration but can potentially lead to identifying novel targets to treat this disease. While this study focuses on SCA1, our approach may be broadly applicable to other SCAs and related neurodegenerative diseases.
