{"doi":"10.1126/scitranslmed.adp5730","title":"Seeding-competent TDP-43 persists in human patient and mouse muscle","abstract":"TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.","journal":"Science Translational Medicine","year":2024,"id":425304,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":489547,"name":"Sara K. Pittman","orcid":null,"position":1,"is_corresponding":false},{"id":832903,"name":"Jil Daw","orcid":"0000-0002-8002-076X","position":2,"is_corresponding":false},{"id":511483,"name":"Chiseko Ikenaga","orcid":"0000-0003-2264-1696","position":3,"is_corresponding":false},{"id":1222944,"name":"Sheng Chen","orcid":"0009-0006-5523-4092","position":4,"is_corresponding":false},{"id":250207,"name":"Dhruva D. Dhavale","orcid":"0000-0002-0096-1085","position":5,"is_corresponding":false},{"id":444031,"name":"Meredith E. Jackrel","orcid":"0000-0003-4406-9504","position":6,"is_corresponding":false},{"id":301613,"name":"Yuna M. Ayala","orcid":"0000-0003-4688-6583","position":7,"is_corresponding":false},{"id":250211,"name":"Paul T. Kotzbauer","orcid":"0000-0001-7155-114X","position":8,"is_corresponding":false},{"id":323467,"name":"Cindy V. Ly","orcid":"0000-0002-7063-5170","position":9,"is_corresponding":false},{"id":254718,"name":"Alan Pestronk","orcid":"0000-0002-8991-5770","position":10,"is_corresponding":false},{"id":257667,"name":"Thomas E. Lloyd","orcid":"0000-0003-4756-3700","position":11,"is_corresponding":false},{"id":420105,"name":"Conrad C. Weihl","orcid":"0000-0002-3816-6124","position":12,"is_corresponding":false},{"id":739722,"name":"Eileen M. Lynch","orcid":"0000-0003-0214-5046","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:58:26.927596Z","pmid":"39602508","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":[]}