Polyglutamine expansion and altered gene expression

描述（由申请人提供）：九种遗传性神经退行性疾病是由相关疾病蛋白中聚谷氨酰胺束的扩张引起的。越来越多的证据表明，亨廷顿病（HD）中含有扩大的聚谷氨酰胺束的亨廷顿蛋白在细胞核中积聚并影响基因表达。转录失调也可能是sc17的主要病理原因，其中TATA结合蛋白（TBP）中存在聚谷氨酰胺扩增。HD和SCA17表现出相似的神经表型和以纹状体和皮层神经变性为特征的神经病理学，表明这两种疾病可能具有相似的病理机制。虽然最近的研究表明突变型亨廷顿蛋白与转录因子Sp1和TAF130结合，但突变型多谷氨酰胺蛋白影响基因表达的机制仍有待研究。此外，目前尚不清楚突变的聚谷氨酰胺蛋白和转录因子之间的异常相互作用如何促进疾病的进程。我们假设可溶性聚谷氨酰胺蛋白在形成大的核包涵体之前通过改变转录因子与其DNA靶点之间的相互作用来干扰基因表达。为了验证这一假设，我们将(1)研究突变的n端亨廷顿蛋白如何异常结合Sp1从而影响基因表达，(2)研究聚谷氨酰胺扩增是否会导致TBP异常结合TATA box及其相关因子，以及(3)研究聚谷氨酰胺扩增是否会导致TBP和亨廷顿蛋白异常结合转录因子TAF130，从而导致一种可能导致HD和SCA17相似神经病理的共同转录缺陷。这些研究旨在深入了解聚谷氨酰胺扩增影响基因表达的机制。它们还将有助于确定治疗多谷氨酰胺疾病的治疗靶点

DESCRIPTION (provided by applicant): Nine inherited neurodegenerative disorders are caused by an expansion of a polyglutamine tract in the associated disease proteins. Increasing evidence indicates that huntingtin containing an expanded polyglutamine tract accumulates in the nucleus and affects gene expression in Huntington disease (HD). Transcriptional dysregulation may also be the major pathological cause in SCA17 in which polyglutamine expansion is present in the TATA binding protein (TBP). HD and SCA17 show similar neurological phenotypes and neuropathology characterized by neurodegeneration in the striatum and cortex, suggesting that both diseases may share a similar pathological mechanism. Although recent studies have shown that mutant huntingtin binds to the transcriptional factors Sp1 and TAF130, the mechanism by which mutant polyglutamine proteins affect gene expression remains to be investigated. Furthermore, it is unclear how the abnormal interactions between mutant polyglutamine proteins and transcription factors contribute to the disease process. We hypothesize that soluble polyglutamine proteins interfere with gene expression by altering the interactions between transcription factors and their DNA targets before the formation of large nuclear inclusions. To test this hypothesis, we will (1) study how mutant N-terminal huntingtin abnormally binds to Sp1 to affect gene expression, (2) investigate whether polyglutamine expansion causes TBP to abnormally bind to the TATA box and its associated factors, and (3) examine whether polyglutamine expansion causes TBP and huntingtin to abnormally bind to the transcriptional factor TAF130, leading to a common transcriptional defect that may contribute to the similar neuropathology in HD and SCA17. These studies aim to provide insights into the mechanism by which polyglutamine expansion affects gene expression. They will also help identify a therapeutic target for the treatment of polyglutamine diseases