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- Title
Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy.
- Authors
Bengoechea, Rocio; Findlay, Andrew R.; Bhadra, Ankan K.; Hao Shao; Stein, Kevin C.; Pittman, Sara K.; Daw, Jil A. W.; Gestwicki, Jason E.; True, Heather L.; Weihl, Conrad C.; Shao, Hao; Daw, Jil Aw
- Abstract
Dominant mutations in the HSP70 cochaperone DNAJB6 cause a late-onset muscle disease termed limb-girdle muscular dystrophy type D1 (LGMDD1), which is characterized by protein aggregation and vacuolar myopathology. Disease mutations reside within the G/F domain of DNAJB6, but the molecular mechanisms underlying dysfunction are not well understood. Using yeast, cell culture, and mouse models of LGMDD1, we found that the toxicity associated with disease-associated DNAJB6 required its interaction with HSP70 and that abrogating this interaction genetically or with small molecules was protective. In skeletal muscle, DNAJB6 localizes to the Z-disc with HSP70. Whereas HSP70 normally diffused rapidly between the Z-disc and sarcoplasm, the rate of diffusion of HSP70 in LGMDD1 mouse muscle was diminished, probably because it had an unusual affinity for the Z-disc and mutant DNAJB6. Treating LGMDD1 mice with a small-molecule inhibitor of the DNAJ-HSP70 complex remobilized HSP70, improved strength, and corrected myopathology. These data support a model in which LGMDD1 mutations in DNAJB6 are a gain-of-function disease that is, counterintuitively, mediated via HSP70 binding. Thus, therapeutic approaches targeting HSP70-DNAJB6 may be effective in treating this inherited muscular dystrophy.
- Subjects
MUSCLE strength; MUSCULAR dystrophy; SKELETAL muscle; LIMB-girdle muscular dystrophy; MUSCLE diseases; PROTEIN metabolism; BIOLOGICAL models; PROTEINS; RESEARCH; MOLECULAR chaperones; NERVE tissue proteins; ANIMAL experimentation; RESEARCH methodology; EVALUATION research; MEDICAL cooperation; YEAST; COMPARATIVE studies; CELLS; RESEARCH funding; MICE; CHEMICAL inhibitors
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 8, p4470
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI136167