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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,3,17]]},"abstract":"<jats:p>\n                    Aggregation and deposition of TAR DNA-binding protein 43 (TDP-43) is a salient pathological signature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration-TDP (FTLD-TDP). TDP-43 proteostasis and aggregation are controlled by several posttranslational modifications, including ubiquitination. While multiple E3 ubiquitin ligases are known to facilitate TDP-43 clearance, little is known about the role of deubiquitinases (DUBs) in controlling TDP-43 proteostasis. Through an unbiased discovery screen of DUBs, here we identify and demonstrate using in vitro and in vivo models, as well as human brain tissue, that ubiquitin-specific peptidase-19 (USP19) acts as a TDP-43-directed DUB that removes K48- and K63-linked ubiquitin conjugates from TDP-43 and preferentially promotes cytoplasmic aggregation of TDP-43 C-terminal fragments (TDP-CTFs) through its catalytic activity. Specifically, the endoplasmic reticulum (ER)-anchored USP19 isoform (USP19-ER) exhibits superior activity in deubiquitinating TDP-CTFs, enhancing its phase separation and aggregation, compared to its cytosolic isoform (USP19-Cyto). Furthermore, as TDP-CTFs are generated at the ER, USP19 acts to couple the aggregation of TDP-CTFs to ER stress (ATF6, ATF4, IRE1, &amp; CHOP). In humans, USP19 protein levels increase in FTLD-TDP brains, which extensively colocalize with cytoplasmic phospho-TDP-43 (pTDP-43) pathology. Importantly, we demonstrate in vivo that genetic reduction of\n                    <jats:italic toggle=\"yes\">usp19<\/jats:italic>\n                    mitigates pTDP-43 pathology, astrogliosis, and ER stress while reversing long-term potentiation (LTP) and motor deficits in a mouse model of TDP-43 pathogenesis (TAR4 mice). These findings establish a critical role of USP19 at the nexus of TDP-43 proteostasis and ER stress, implicating its pathogenic role in FTLD-TDP and ALS.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2514355123","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T17:47:37Z","timestamp":1773164857000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress"],"prefix":"10.1073","volume":"123","author":[{"given":"Yan","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4140-6341","authenticated-orcid":false,"given":"Teresa R.","family":"Kee","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khoi D.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunkyoung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6437-8892","authenticated-orcid":false,"given":"Tian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8394-7563","authenticated-orcid":false,"given":"Simon S.","family":"Wing","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology and Metabolism, Research Institute of the McGill University Health Centre, McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9194-1361","authenticated-orcid":false,"given":"Jung-A A","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7132-821X","authenticated-orcid":false,"given":"David E.","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University","place":["Cleveland"]},{"name":"Louis Stokes Cleveland Veterans Affairs Medical Center","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.10.093"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e31817713b5"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0081170"},{"key":"e_1_3_4_5_2","first-page":"754","article-title":"Stress signaling from the endoplasmic reticulum: A central player in the pathogenesis of amyotrophic lateral sclerosis","volume":"63","author":"Walker A. 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