{"doi":"10.1242/dmm.049323","title":"TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic <i>Caenorhabditis elegans</i>","abstract":"Although amyloid β (Aβ) and tau aggregates define the neuropathology of Alzheimer's disease (AD), TDP-43 has recently emerged as a co-morbid pathology in more than half of patients with AD. Individuals with concomitant Aβ, tau and TDP-43 pathology experience accelerated cognitive decline and worsened brain atrophy, but the molecular mechanisms of TDP-43 neurotoxicity in AD are unknown. Synergistic interactions among Aβ, tau and TDP-43 may be responsible for worsened disease outcomes. To study the biology underlying this process, we have developed new models of protein co-morbidity using the simple animal Caenorhabditis elegans. We demonstrate that TDP-43 specifically enhances tau but not Aβ neurotoxicity, resulting in neuronal dysfunction, pathological tau accumulation and selective neurodegeneration. Furthermore, we find that synergism between tau and TDP-43 is rescued by loss-of-function of the robust tau modifier sut-2. Our results implicate enhanced tau neurotoxicity as the primary driver underlying worsened clinical and neuropathological phenotypes in AD with TDP-43 pathology, and identify cell-type specific sensitivities to co-morbid tau and TDP-43. Determining the relationship between co-morbid TDP-43 and tau is crucial to understand, and ultimately treat, mixed pathology AD.","journal":"Disease Models & Mechanisms","year":2022,"id":246069,"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":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":881798,"name":"Jade G. Stair","orcid":"0000-0002-3120-7069","position":1,"is_corresponding":false},{"id":881799,"name":"Joshua C. Hincks","orcid":"0000-0001-7852-737X","position":2,"is_corresponding":false},{"id":881800,"name":"Heather N. Currey","orcid":"0000-0001-6428-4880","position":3,"is_corresponding":false},{"id":262865,"name":"Thomas D. Bird","orcid":"0000-0001-9598-3529","position":4,"is_corresponding":false},{"id":38380,"name":"C. Dirk Keene","orcid":"0000-0002-5291-1469","position":5,"is_corresponding":false},{"id":351412,"name":"Brian C. Kraemer","orcid":"0000-0002-2252-7634","position":6,"is_corresponding":false},{"id":355965,"name":"Nicole F. Liachko","orcid":"0000-0003-1250-3871","position":7,"is_corresponding":false},{"id":363970,"name":"Caitlin S. Latimer","orcid":"0000-0003-3727-4278","position":0,"is_corresponding":true}],"reference_count":99,"raw_metadata":null,"created_at":"2026-07-19T00:23:43.438539Z","pmid":"35178571","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":[]}