Cellular pathways underlying polyglutamine degeneration

描述（由申请人提供）：我们的实验室旨在了解脊髓小脑共济失调1型（SCA 1）的生物学，SCA 1是一种神经退行性疾病，属于疾病蛋白中多聚谷氨酰胺（polyQ）道扩张引起的疾病家族。在SCA 1中，多聚谷氨酰胺重复扩增发生在蛋白共济失调蛋白-1中。先前的研究已经确定，扩展的polyQ束改变了共济失调蛋白-1的构象、清除率以及与天然伴侣蛋白形成复合物的能力。然而，在生命的前两周内，在行为或退行性病变明显之前很久，突变型共济失调蛋白-1破坏了特定基因的转录。虽然目前还不清楚这是如何发生的，但我们已经发现了一种可能的机制：我们发现SCA 1小鼠的小脑表现出组蛋白的低乙酰化，特别是在下调基因的启动子处。组蛋白的这种翻译后修饰与转录抑制相关。有趣的是， 我们假设突变型共济失调蛋白-1通过募集这些辅阻遏物引起靶基因的病理性阻遏而引起转录抑制。我们的初步研究结果支持这一假设，并表明，遗传上消除这些辅阻遏物（LANP）之一，改善了共济失调表型和SCA 1基因敲入小鼠的神经病理学。为了更好地理解这些辅阻遏物在SCA 1发病机制中的作用，我们提出了以下目标：（1）用一系列行为、运动和神经病理学测定来表征缺乏LANP的Sca 1154 Q/2 Q小鼠，以描绘SCA 1表型因LANP缺失而改善的方面;（2）阐明组蛋白去乙酰化酶HDAC 3对浦肯野细胞功能和SCA 1病理学的贡献;以及（3）鉴定共济失调蛋白-1抑制的直接靶点并机械地探测共济失调蛋白-1如何调节基因表达。

DESCRIPTION (provided by applicant): Our lab seeks to understand the biology of spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that belongs to the family of disorders caused by the expansion of a polyglutamine (polyQ) tract in the disease protein. In SCA1 the polyglutamine repeat expansion occurs in the protein ataxin-1. Previous studies have established that the expanded polyQ tract alters ataxin-1's conformation, clearance, and ability to form complexes with native partner proteins. Within the first two weeks of life, however, long before behavioral or degenerative pathology is apparent, mutant ataxin-1 disrupts the transcription of specific genes. Although it is still unclear how this happens, we have uncovered one likely mechanism: we have found that cerebella of SCA1 mice exhibit hypoacetylation of histones, particularly at the promoters of down-regulated genes. This post-translational modification of histones is correlated with transcriptional repression. It is intriguing that We hypothesize that mutant ataxin-1 causes transcriptional repression by recruiting these corepressors to cause pathologic repression of target genes. Our preliminary findings support this hypothesis and suggest that genetically depleting one of these corepressors (LANP) improves both the ataxic phenotype and the neuropathology of SCA1 knock-in mice. To better understand the role of these corepressors in SCA1 pathogenesis we propose the following aims: (1) Characterize Sca1154Q/2Q mice lacking LANP with a range of behavioral, motor, and neuropathological assays to delineate the facets of the SCA1 phenotype improved by loss of LANP; (2) Elucidate the contribution of the histone deacetylase HDAC3 to Purkinje cell function and SCA1 pathology; and (3) Identify the direct targets of ataxin-1 repression and mechanistically probe how ataxin-1 modulates gene expression.