Chaperone Dysfunction in Myopathy: Connecting Yeast Genetics with Mouse Models

 描述(申请人提供)：蛋白质聚集体存在于年龄相关的退行性疾病中，包括衰弱的肌病和肌肉营养不良。当蛋白质错误折叠、自我组装并逃避降解时，它们就会形成。蛋白质伴侣，或热休克蛋白(HSPs)，防止蛋白质的有毒错误折叠和聚集。因此，伴侣网络的突变或缺陷会导致疾病。最近，我们发现Hsp40辅助伴侣基因DNAJB6在一种遗传性显性包涵体肌病(IBM)中发生突变，又称肢带型肌营养不良1D(LGMD1D)(1)。LGMD1D是一种进行性晚发性肌营养不良症。这项建议将利用多学科方法，协同研究哺乳动物细胞生物学和酵母模型，以了解DNAJB6突变在退行性肌病中的作用。该建议的目标是1)确定DNAJB6在骨骼肌中的作用和建立LGMD1D模型；2)探讨DNAJB6中的LGMD1D突变对酵母和哺乳动物细胞中的Prion和Prion样聚集的作用；3)确定LGMD1D突变功能障碍的分子机制并筛选潜在的修饰物。共同研究人员非常适合并将补充这些关于LGMD1D机制的创新研究。

 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.