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是由单个基因中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，其具有超过临界计数的扩展的多聚谷氨酰胺（polyQ）延伸。随着疾病的进展，polyQ的较长延伸导致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htt（mhtt）的错误折叠，导致mhtt的积累和沉积，干扰神经元的功能和活力。然而，mhtt错误折叠如何导致神经元功能障碍和神经退行性变仍然不清楚。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。它们被募集到人类HD脑中突变htt聚集的位点。当在HD动物模型中过表达时，分子伴侣抑制神经变性，并且当通过遗传方法删除时，它们加剧发病机制。基于这些结果，我推测，错误折叠的mhtt可能会隔离内源性分子伴侣的方式，阻止他们进行他们的正常功能，从而有助于HD的发病机制。这项研究的主要目的是确定错误折叠的mhtt是否会导致分子伴侣的“正常管家”功能的全面损害。识别在HD中失调的分子伴侣介导的通路可能为这种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.