Polyglutamine expansion and altered gene expression

描述（由申请人提供）：9种遗传性神经退行性疾病是由相关疾病蛋白中多聚谷氨酰胺束的扩张引起的。越来越多的证据表明，亨廷顿蛋白含有一个扩大的多聚谷氨酰胺道积累在细胞核中，并影响基因表达的亨廷顿病（HD）。转录失调也可能是SCA17的主要病理原因，其中TATA结合蛋白（TBP）中存在多聚谷氨酰胺扩增。HD和SCA17显示出相似的神经学表型和神经病理学，其特征在于纹状体和皮质中的神经变性，这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，突变亨廷顿蛋白结合转录因子Sp1和TAF130，突变聚谷氨酰胺蛋白影响基因表达的机制仍有待研究。此外，目前还不清楚突变的多聚谷氨酰胺蛋白和转录因子之间的异常相互作用如何促成疾病过程。我们假设可溶性多聚谷氨酰胺蛋白通过改变转录因子和它们的DNA靶之间的相互作用来干扰基因表达，然后形成大的核内含物。为了验证这一假设，我们将（1）研究突变的N-末端亨廷顿蛋白如何异常结合Sp1以影响基因表达，（2）研究多聚谷氨酰胺扩增是否导致TBP异常结合TATA盒及其相关因子，（3）研究多聚谷氨酰胺扩增是否导致TBP和亨廷顿蛋白异常结合转录因子TAF130，导致共同的转录缺陷，这可能导致HD和SCA17中相似的神经病理学。这些研究旨在深入了解多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聚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