Understanding the Cellular Basis of Movement Disorders

项目摘要 脊髓小脑性共济失调1型（SCA 1）是一种由CAG引起的常染色体显性遗传性神经退行性疾病 ATXN 1中的三核苷酸重复扩增，导致ATXN 1中异常长的多聚谷氨酰胺束。 随后的蛋白质，共济失调蛋白-1（ATXN 1）。突变体ATXN 1具有错误折叠的倾向，抵抗细胞降解， 毒性也会随着浓度的增加而增加有证据表明，这种毒性是通过一种功能增强机制发生的 指出转录紊乱是早期症状前的致病事件。我们最近发现 浦肯野细胞（SCA 1中最脆弱的细胞）最早的异常不是由细胞引起的， 自主变化，但在非细胞自主的方式通过影响小脑的增殖和命运， 产后干细胞在本提案中，我们将检验以下假设，即潜在的SCA 1病理学具有其 根源于早期的发展过程，如果这些缺陷被克服，人们可能能够延迟或 改善以后的神经变性，从而为治疗这种目前无法治疗的病症铺平了道路。

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.