Analysis of Hsp70 and Hsp90 function in Huntington´s disease: A potential therapeutic target

亨廷顿病(HD)是一种遗传性神经退行性疾病。HD是由单个基因的常染色体显性突变引起的，该突变导致亨廷顿蛋白(HTT)的表达，同时扩展的聚谷氨酰胺(PolyQ)伸展到临界计数以上。随着疾病的发展，较长的多聚Q会导致HTT聚集并形成细胞内包涵体。一种可能的致病机制涉及突变的HTT(MHTT)的错误折叠导致mHTT的积累和沉积，从而干扰神经元的功能和生存。然而，mHTT错误折叠如何导致神经元功能障碍和神经变性仍不清楚。分子伴侣对于其他蛋白质的正确折叠是必不可少的，并且在进化过程中高度保守。它们被招募到人类HD大脑中突变的HTT聚集位点。当在HD动物模型中过度表达时，分子伴侣抑制神经退行性变，当通过遗传方法缺失时，它们加剧了发病。基于这些结果，我推测错误折叠的mHTT可能以一种阻止内源性分子伴侣发挥其正常功能的方式隔离了内源性分子伴侣，从而促进了HD的发病。这项拟议的研究的主要目标是确定错误折叠的mHTT是否会导致分子伴侣的“正常管家”功能的整体损害。识别HD中调节失调的伴侣介导的通路可能为这一毁灭性和致命性疾病提供新的治疗见解。

Huntington’s disease (HD) is a hereditary neurodegenerative disorder. HD is caused by an autosomal dominant mutation in a single gene that leads to the expression of the protein huntingtin (htt) with an expanded polyglutamine (polyQ) stretch above a critical count. Longer stretches of polyQ cause htt to aggregate and form intracellular inclusions as the disease progresses. One possible pathogenic mechanism involves misfolding of mutant htt (mhtt) leading to the accumulation and deposition of mhtt that interferes with neuronal function and viability. However, how mhtt misfolding causes neuronal dysfunction and neurodegeneration is still unclear. Molecular chaperones are essential for the proper folding of other proteins and are highly conserved through evolution. They are recruited to sites of mutant htt aggregation in human HD brains. When overexpressed in animal models of HD, molecular chaperones suppress neurodegeneration, and when deleted by genetic approaches, they exacerbate pathogenesis. Based on these results, I hypothesize that misfolded mhtt may sequester endogenous molecular chaperones in a manner that prevents them from carrying out their normal function, thus contributing to HD pathogenesis. The major goal of the proposed study is to determine whether misfolded mhtt leads to a global impairment of the “normal housekeeping” functions of molecular chaperones. Identifying chaperone-mediated pathways that are dysregulated in HD may provide new therapeutic insights into this devastating and fatal disease.