{"doi":"10.1371/journal.pgen.1011518","title":"Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis","abstract":"Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell. The heat shock responsive chaperone Hsp90 has been shown to interact with TDP-43 and stabilize its normal conformation; however, it is not known whether this interaction contributes to neurotoxicity in vivo. Using a C. elegans model of fALS mutant TDP-43 proteinopathy, we find that loss of function of HSP-90 protects against TDP-43 neurotoxicity and subsequent neurodegeneration in adult animals. This protection is accompanied by a decrease in both total and phosphorylated TDP-43 protein. We also find that hsp-90 mutation or inhibition upregulates key stress responsive heat shock pathway gene expression, including hsp-70 and hsp-16.1, and we demonstrate that normal levels of hsp-16.1 are required for hsp-90 mutation effects on TDP-43. We also observe that the neuroprotective effect due to HSP-90 dysfunction does not involve direct regulation of proteasome activity in C. elegans. Our data demonstrate for the first time that Hsp90 chaperone activity contributes to adverse outcomes in TDP-43 proteinopathies in vivo using a whole animal model of ALS.","journal":"PLoS Genetics","year":2024,"id":428805,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9415,"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":881800,"name":"Heather N. Currey","orcid":"0000-0001-6428-4880","position":1,"is_corresponding":false},{"id":881799,"name":"Joshua C. Hincks","orcid":"0000-0001-7852-737X","position":2,"is_corresponding":false},{"id":881798,"name":"Jade G. Stair","orcid":"0000-0002-3120-7069","position":3,"is_corresponding":false},{"id":656386,"name":"Nicolas J. Lehrbach","orcid":"0000-0001-7342-4136","position":4,"is_corresponding":false},{"id":355965,"name":"Nicole F. Liachko","orcid":"0000-0003-1250-3871","position":5,"is_corresponding":false},{"id":1230919,"name":"Laura García‐Toscano","orcid":null,"position":0,"is_corresponding":true}],"reference_count":110,"raw_metadata":null,"created_at":"2026-07-19T01:59:02.165535Z","pmid":"39724103","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":[]}