{"doi":"10.1172/jci182088","title":"TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia","abstract":"Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from an RNA-Seq (DaPars) tool to ALS/FTD transcriptome datasets and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional relevance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3' UTRs, corresponding with a change in the subcellular distribution of MARK3 and increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously understudied feature of TDP-43-driven disease pathology in ALS/FTD and highlight a potentially important mechanistic link between TDP-43 dysfunction and tau regulation.","journal":"Journal of Clinical Investigation","year":2025,"id":510011,"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":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":52933,"name":"Ya Cui","orcid":"0000-0003-1574-0928","position":1,"is_corresponding":false},{"id":1027915,"name":"Sebastian Michels","orcid":"0000-0002-9265-9034","position":2,"is_corresponding":false},{"id":1366027,"name":"Michael R. 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Tam","orcid":"0000-0002-1023-3655","position":11,"is_corresponding":false},{"id":1365248,"name":"Sneha Menon","orcid":"0000-0003-1079-8928","position":12,"is_corresponding":false},{"id":1366028,"name":"W. Situ","orcid":null,"position":13,"is_corresponding":false},{"id":1366029,"name":"Saira L Cazarez","orcid":null,"position":14,"is_corresponding":false},{"id":1365249,"name":"Ali Shahidi Zandi","orcid":"0000-0002-3080-4603","position":15,"is_corresponding":false},{"id":1366030,"name":"Kean C. K. Ehsani","orcid":null,"position":16,"is_corresponding":false},{"id":1366031,"name":"Sierra Howard","orcid":null,"position":17,"is_corresponding":false},{"id":54753,"name":"Dennis W. Dickson","orcid":"0000-0001-7189-7917","position":18,"is_corresponding":false},{"id":345342,"name":"Molly Hammell","orcid":"0000-0003-0405-8392","position":19,"is_corresponding":false},{"id":238155,"name":"Mercedes Prudencio","orcid":"0000-0002-4894-4858","position":20,"is_corresponding":false},{"id":228616,"name":"Leonard Petrucelli","orcid":"0000-0003-2959-129X","position":21,"is_corresponding":false},{"id":488508,"name":"Wei Li","orcid":"0000-0001-7530-3485","position":22,"is_corresponding":false},{"id":241296,"name":"Albert R. La Spada","orcid":"0000-0001-6151-2964","position":23,"is_corresponding":false},{"id":486977,"name":"Frederick J. 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