{"doi":"10.1172/jci136167","title":"Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy","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.","journal":"Journal of Clinical Investigation","year":2020,"id":99192,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":488514,"name":"Andrew R. Findlay","orcid":"0000-0002-8728-9833","position":1,"is_corresponding":false},{"id":488515,"name":"Ankan K. Bhadra","orcid":"0000-0002-8679-0984","position":2,"is_corresponding":false},{"id":364716,"name":"Hao Shao","orcid":"0000-0003-4437-5536","position":3,"is_corresponding":false},{"id":488516,"name":"Kevin C. Stein","orcid":"0000-0002-0622-8319","position":4,"is_corresponding":false},{"id":489547,"name":"Sara K. Pittman","orcid":null,"position":5,"is_corresponding":false},{"id":489548,"name":"Jill Daw","orcid":null,"position":6,"is_corresponding":false},{"id":275686,"name":"Jason E. Gestwicki","orcid":"0000-0002-6125-3154","position":7,"is_corresponding":false},{"id":420106,"name":"Heather L. True","orcid":"0000-0003-4824-9529","position":8,"is_corresponding":false},{"id":420105,"name":"Conrad C. Weihl","orcid":"0000-0002-3816-6124","position":9,"is_corresponding":false},{"id":488513,"name":"Rocío Bengoechea","orcid":"0000-0002-9029-019X","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-18T22:37:35.547042Z","pmid":"32427588","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}