Cellular pathways underlying polyglutamine degeneration

描述(申请人提供)：我们的实验室试图了解脊髓小脑性共济失调1型(SCA1)的生物学，这是一种神经退行性疾病，属于疾病蛋白中聚谷氨酰胺(PolyQ)束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。以前的研究已经证实，扩展的多Q区改变了ataxin-1‘S的构象、清除性和与天然伴侣蛋白形成复合体的能力。然而，在生命的头两周内，在行为或退行性病变显现之前很久，突变的ataxin-1就扰乱了特定基因的转录。虽然目前还不清楚这是如何发生的，但我们已经发现了一个可能的机制：我们已经发现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上。组蛋白的这种翻译后修饰与转录抑制相关。耐人寻味的是，我们假设突变的ataxin-1通过招募这些辅阻遏子导致靶基因的病理性抑制而导致转录抑制。我们的初步发现支持这一假说，并表明基因耗尽其中一个辅阻遏子(LANP)可以改善SCA1基因敲入小鼠的共济失调表型和神经病理。为了更好地了解这些辅抑制子在SCA1发病机制中的作用，我们提出了以下目标：(1)用一系列行为、运动和神经病理学方法对缺乏LANP的Sca1154Q/2Q小鼠进行鉴定，以描绘因LANP缺失而改善的SCA1表型的各个方面；(2)阐明组蛋白去乙酰基酶HDAC3对Purkinje细胞功能和SCA1病理的贡献；以及(3)确定ataxin-1抑制的直接靶点并从机制上探讨ataxin-1如何调节基因表达。 公共卫生相关性：脊髓小脑性共济失调1型(SCA1)是一种成人起病的神经退行性疾病，其特征是小脑和脑干的恶化。在这个建议中，我们试图阐明基因表达变化的潜在机制，这是SCA1的一个标志。最终目标是利用这些洞察力开发合理的疗法来治疗这种无情且无法治愈的遗传病患者。

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.