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

Ataxin-1 与 SCA1 中 RORalpha 复合物的相互作用

• 批准号: 7111454
• 负责人: KRISTIN Marie GEHRKING
• 金额: $ 3.59万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111454
• 关键词: alleles; ataxia; family; genetically modified animals; homopeptide; hormone receptor; laboratory mouse; model; mutant; proteins

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.

描述（由申请人提供）： 脊髓小脑共济失调 1 型 (SCA1) 是一种常染色体显性神经退行性疾病，由 SCA1 编码的蛋白质 ataxin-1 内的 CAG 三核苷酸扩增引起。 SCA1 是九种多聚谷氨酰胺疾病家族之一，其中包括亨廷顿舞蹈病。随着 SCA1 的进展，浦肯野细胞变性会导致小脑症状，包括步态异常和协调性丧失。先前的研究表明，小脑的正常发育是由核激素受体 RORalpha 协调的。此外，RORalpha 和 ataxin-1 在体内相互作用并共享一组共同的信号传导靶标。 SCA1 小鼠中浦肯野细胞 RORα 水平降低，但可以通过关闭 ataxin-1 表达来挽救，这表明 RORα 在预防 SCA1 发病机制中发挥作用。本研究的目标是确定 RORalpha 的缺失是否会加剧与 SCA1 相关的变性，从而为该类神经退行性疾病提供新的治疗靶点。