{"doi":"10.7554/elife.85921.2","title":"RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy","abstract":"Abstract TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic-acid binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.","journal":"eLife","year":2023,"id":395081,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":11659,"name":"Jeremy M. Simon","orcid":"0000-0003-3906-1663","position":1,"is_corresponding":false},{"id":821752,"name":"Baggio Evangelista","orcid":"0000-0002-4166-3068","position":2,"is_corresponding":false},{"id":280529,"name":"Youjun Chen","orcid":"0000-0002-6484-2325","position":3,"is_corresponding":false},{"id":701951,"name":"Xu Tian","orcid":"0009-0002-2109-9866","position":4,"is_corresponding":false},{"id":998707,"name":"Sara Nafees","orcid":null,"position":5,"is_corresponding":false},{"id":600923,"name":"Ariana Marquez Gonzalez","orcid":"0000-0002-0398-1794","position":6,"is_corresponding":false},{"id":1079598,"name":"Huijun Jiang","orcid":"0000-0002-7918-8805","position":7,"is_corresponding":false},{"id":500721,"name":"Ping Wang","orcid":"0000-0002-6298-2922","position":8,"is_corresponding":false},{"id":280527,"name":"Deepa Ajit","orcid":"0000-0002-6062-7070","position":9,"is_corresponding":false},{"id":443723,"name":"Viktoriya D. Nikolova","orcid":"0000-0003-0404-8602","position":10,"is_corresponding":false},{"id":382906,"name":"Kathryn M. Harper","orcid":"0000-0002-6297-0032","position":11,"is_corresponding":false},{"id":269877,"name":"J. Ashley Ezzell","orcid":"0000-0002-5142-4685","position":12,"is_corresponding":false},{"id":381755,"name":"Feng‐Chang Lin","orcid":"0000-0002-2638-1775","position":13,"is_corresponding":false},{"id":533122,"name":"Adriana S. Beltrán","orcid":"0000-0002-7774-3190","position":14,"is_corresponding":false},{"id":275071,"name":"Sheryl S. Moy","orcid":"0000-0001-7318-7900","position":15,"is_corresponding":false},{"id":280536,"name":"Todd J. Cohen","orcid":"0000-0002-4099-0278","position":16,"is_corresponding":false},{"id":731528,"name":"Julie Necarsulmer","orcid":"0000-0002-0669-2023","position":0,"is_corresponding":true}],"reference_count":185,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:18.686170Z","pmid":null,"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":[]}