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性共济失调1型（SCA1）的生物学，SCA1是一种神经退行性疾病，属于由疾病蛋白中聚谷氨酰胺（polyQ）通道扩张引起的疾病家族。在SCA1中，聚谷氨酰胺重复扩增发生在蛋白ataxin-1中。先前的研究已经证实，扩展的多q通道改变了ataxin-1的构象、清除和与天然伴侣蛋白形成复合物的能力。然而，在出生后的前两周，在行为或退行性病理出现之前，突变的ataxin-1会破坏特定基因的转录。尽管尚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SCA1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。组蛋白的翻译后修饰与转录抑制有关。有趣的是，我们假设突变的ataxin-1通过招募这些辅抑制因子引起靶基因的病理抑制而引起转录抑制。我们的初步研究结果支持这一假设，并表明基因上消耗其中一种共抑制因子（LANP）可以改善SCA1敲入小鼠的共济失调表型和神经病理学。为了更好地理解这些共抑制因子在SCA1发病机制中的作用，我们提出以下目标：(1)通过一系列行为、运动和神经病理学检测来表征缺乏LANP的sc1154q /2Q小鼠，以描述LANP缺失改善的SCA1表型的各个方面；(2)阐明组蛋白去乙酰化酶HDAC3在浦肯野细胞功能和SCA1病理中的作用；(3)确定ataxin-1抑制的直接靶点，探索ataxin-1调控基因表达的机制。

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. PUBLIC HEALTH RELEVANCE: Spinocerebellar Ataxia Type 1 (SCA1) is an adult onset neurodegenerative disease characterized by deterioration of the cerebellum and the brainstem. In this proposal we seek to elucidate mechanisms underlying changes in gene expression, a hallmark of SCA1. The ultimate goal is to use these insights to develop rational therapies to treat patients suffering from this relentless and incurable genetic disease.