{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T11:16:38Z","timestamp":1792149398342,"version":"4.4.0"},"reference-count":55,"publisher":"American Society for Clinical Investigation","issue":"11","license":[{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS122140,AG000096,CA193466,NS118570"],"award-info":[{"award-number":["NS122140,AG000096,CA193466,NS118570"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS122140,AG000096,CA193466,NS118570"],"award-info":[{"award-number":["NS122140,AG000096,CA193466,NS118570"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,2]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>MARK3<\/jats:italic>\n                    transcripts with longer 3\u2032 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\u2013driven disease pathology in ALS\/FTD and highlight a potentially important mechanistic link between TDP-43 dysfunction and tau regulation.\n                  <\/jats:p>","DOI":"10.1172\/jci182088","type":"journal-article","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T14:00:41Z","timestamp":1748786441000},"source":"Crossref","is-referenced-by-count":30,"title":["TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia"],"prefix":"10.1172","volume":"135","author":[{"given":"Frederick J.","family":"Arnold","sequence":"first","affiliation":[{"name":"Department of Pathology & Laboratory Medicine 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