Chaperone Dysfunction in Myopathy: Connecting Yeast Genetics with Mouse Models

 描述（由申请人提供）：蛋白质聚集体存在于年龄相关性退行性疾病中，包括衰弱性肌病和肌营养不良症。它们是在蛋白质错误折叠、自我组装和逃避降解时形成的。蛋白质伴侣，或热休克蛋白（HSP），防止有毒的错误折叠和蛋白质聚集。因此，伴侣蛋白网络中的突变或缺陷导致疾病。最近，我们发现，DNAJB 6，一种HSP 40辅助分子伴侣，在显性遗传包涵体肌病（IBM）中发生突变，也称为肢带型肌营养不良1D（LGMD 1D）（1）。LGMD 1D是一种进行性迟发性肌营养不良症。该提案将利用多学科方法，协同研究哺乳动物细胞生物学和酵母模型，以了解DNAJB 6突变体在退行性肌病中的作用。本研究的目的是：1）确定DNAJB 6在骨骼肌中的作用并建立LGMD 1D模型; 2）探索DNAJB 6中LGMD 1D突变对酵母和哺乳动物细胞中朊病毒和朊病毒样聚集的作用; 3）确定LGMD 1D突变功能障碍的分子机制并筛选潜在的修饰剂。共同研究者非常适合并将相互补充这些关于LGMD 1D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.