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.
Muscular dystrophies are a disabling and often fatal form of hereditary muscle disease. No proven therapies exist for many forms. This study will explore the pathogenesis of limb girdle muscular dystrophy type 1D (LGMD1D) due to mutations in the protein chaperone DNAJB6. Understanding DNAJB6 function in skeletal muscle and protein aggregation is important for LGMD1D and other forms of muscle weakness.
| Meister-Broekema, Melanie; Freilich, Rebecca; Jagadeesan, Chandhuru et al. (2018) Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks. Nat Commun 9:5342 |
| Lee, YouJin; Jonson, Per Harald; Sarparanta, Jaakko et al. (2018) TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations. J Clin Invest 128:1164-1177 |
| Güttsches, Anne-Katrin; Brady, Stefen; Krause, Kathryn et al. (2017) Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis. Ann Neurol 81:227-239 |
| Bengoechea, Rocio; Pittman, Sara K; Tuck, Elizabeth P et al. (2015) Myofibrillar disruption and RNA-binding protein aggregation in a mouse model of limb-girdle muscular dystrophy 1D. Hum Mol Genet 24:6588-602 |
| Udan-Johns, Maria; Bengoechea, Rocio; Bell, Shaughn et al. (2014) Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones. Hum Mol Genet 23:157-70 |
| Stein, Kevin C; Bengoechea, Rocio; Harms, Matthew B et al. (2014) Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers. J Biol Chem 289:21120-30 |
