The Interaction of Ataxin-1 with the RORalpha Complex in SCA1

描述(由申请人提供)： 脊髓小脑性共济失调1型(SCA1)是一种常染色体显性遗传性神经退行性疾病，由SCA1编码蛋白ataxin-1内的CAG三核苷酸扩增引起。SCA1是包括亨廷顿氏病在内的九种多谷氨酰胺疾病家族之一。随着SCA1的进展，浦肯野细胞变性会引起小脑症状，包括步态异常和协调性丧失。先前的研究已经表明，小脑的正常发育是由核激素受体RORpha协调的。此外，RORpha和ataxin-1在体内相互作用，并共享一组共同的信号靶点。在SCA1小鼠中，浦肯野细胞RORpha的水平降低，但可以通过关闭ataxin-1的表达来挽救，这表明RORpha在预防SCA1的发病中发挥了作用。这项研究的目的是确定RORpha的缺失是否会加剧与SCA1相关的变性，为这一家族神经退行性疾病提供新的治疗靶点。

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion within the SCA1-encoded protein ataxin-1. SCA1 is one of a family of nine polyglutamine diseases, including Huntington's disease. As SCA1 progresses, Purkinje cell degeneration causes cerebellar symptoms, including gait abnormalities and loss of coordination. Previous work has shown that proper cerebellar development is coordinated by RORalpha, a nuclear hormone receptor. Furthermore, RORalpha and ataxin-1 interact in vivo and share a common set of signaling targets. Purkinje cell RORalpha levels are decreased in SCA1 mice, but can be rescued by turning off ataxin-1 expression, suggesting a role for RORalpha in the prevention of SCA1 pathogenesis. This goal of this research is to determine whether loss of RORalpha exacerbates the degeneration associated with SCA1, providing new therapeutic targets for this family of neurodegenerative diseases.