Understanding the Cellular Basis of Movement Disorders

项目摘要 脊髓小脑性共济失调1型(SCA1)是一种由CAG引起的常染色体显性遗传性神经退行性疾病 ATXN1中的三核苷酸重复扩增导致在TXN1中存在异常长的聚谷氨酰胺束 随后的蛋白质，ataxin-1(ATXN1)。突变的ATXN1有错误折叠的倾向，抵抗细胞降解， 随着其水平的上升，毒性也会增加。这种毒性是通过一种作用机制而发生的，有证据表明 指出转录紊乱是一种早期的症状前致病事件。我们最近发现 浦肯野细胞(SCA1中最脆弱的细胞)最早的异常不是由细胞- 通过影响小脑的增殖和命运而以非细胞自主方式发生的自主性变化 出生后干细胞。在这个提案中，我们将测试以下假设：潜在的SCA1病理具有 根植于早期发育过程，如果这些缺陷被克服，人们可能能够延迟或 改善后来的神经退化，从而为这种目前无法治愈的疾病的治疗铺平道路。

Project Summary 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.