Intra-Regional Differences in Cerebellar Vulnerability of Spinocerebellar Ataxia Type 1 Mice

Abstract

Increasing evidence demonstrates distinct regional differences across the cerebellum, yet whether these differences contribute to selective vulnerability in cerebellar disease remains an open question. Spinocerebellar Ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by an abnormal expansion of polyglutamine (polyQ) repeats in the ATAXIN1 (ATXN1) gene and characterized by cerebellar degeneration. Recent studies in patients with SCA1 indicate that pathogenesis is not uniform across the cerebellum, with posterior vermis and hemispheres exhibiting worse pathology. Mouse models of SCA1 have been critical to increasing our understanding of mutant ATXN1 toxicity, however most studies only assessed cerebellar degeneration from one lobule or with bulk cerebellar tissue.As a consequence, a question that remains unanswered is whether regions of the cerebellum undergo distinct pathological alterations across distinct regions and, if so, what molecular and functional mechanism underlie those differences in mouse models of SCA1. To address this gap in knowledge, I sought to investigate SCA1 pathology across distinct cerebellar regions in a mouse model of SCA1. I hypothesized that SCA1 knock-in mice will exhibit increased vulnerability of the posterior vermis and hemispheres, that these differences in pathology will correlate with underlying distinct gene expression changes, and will result in functional impairment that will be larger in more vulnerable PCs. My results indicate non- uniform degeneration with exacerbated Purkinje cell atrophy and gliosis in the posterior vermis. Importantly, I identified region-enriched genes and pathways of pathogenesis that may contribute to resistance and vulnerability to SCA1 pathogenesis across the cerebellar cortex. I found that calcium activity of Purkinje cells is significantly altered in posterior but not anterior vermis, indicating that worse molecular and pathological changes correlate with functional alterations. Finally, I also found unique genes and pathways altered in the DCN. This work highlights the importance of examining the cerebellum on a regional level in order to better understand disease pathology.