Understanding the Cellular Basis of Movement Disorders

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion in ATXN1 that leads to an abnormally long polyglutamine tract in the subsequent protein, ataxin-1 (ATXN1). Mutant ATXN1 has a propensity to misfold, resist cellular degradation, and increase in toxicity as its levels rise. This toxicity occurs by a gain of function mechanism with evidence point to transcriptional derangements as an early, presymptomatic pathogenic event. We recently discovered that the earliest abnormalities in Purkinje cells (cells that are most vulnerable in SCA1) are not caused by cell-autonomous changes but in a non-cell autonomous manner by affecting the proliferation and fate of cerebellar post-natal stem cells. In this proposal, we will test the hypothesis that the underlying SCA1 pathology has its roots in early developmental processes and that if these defects are overcome one might be able to delay or ameliorate later neurodegeneration, thus paving the way for therapy for this currently untreatable condition.