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

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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.