Chaperone Dysfunction in Myopathy: Connecting Yeast Genetics with Mouse Models

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 DESCRIPTION (provided by applicant): Protein aggregates are present in age-associated degenerative disease, including debilitating myopathies and muscular dystrophies. They form when proteins misfold, self-assemble and elude degradation. Protein chaperones, or heat shock proteins (HSPs), protect against the toxic misfolding and aggregation of proteins. Hence, mutations or deficiencies in the chaperone network lead to disease. Recently, we found that DNAJB6, an HSP40 co-chaperone, is mutated in a dominantly inherited inclusion body myopathy (IBM) also named limb- girdle muscular dystrophy type 1D (LGMD1D) (1). LGMD1D is a progressive late onset muscular dystrophy. This proposal will utilize a multidisciplinary approach that synergizes studies mammalian cell biology, and yeast models to understand the role of DNAJB6 mutants in a degenerative myopathy. The goals of this proposal are to 1) define the role of DNAJB6 in skeletal muscle and model LGMD1D; 2) explore the role of LGMD1D mutations in DNAJB6 on prion and prion like aggregation in yeast and mammalian cells and 3) define the molecular mechanism of LGMD1D mutant dysfunction and screen for potential modifiers. The co- investigators are well suited and will complement each other these innovative studies on the mechanism of LGMD1D.