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Dysregulated TDP-43 causes motor neuron loss, highlighting the need for proper expression levels. Here, we identify a dominant-negative isoform among the multiple TARDBP splicing variants and validate its endogenous expression using a developed antibody against its translated product. Furthermore, we revealed that ALS-associated RBPs regulate its expression: hnRNP K promotes its splicing and expression, while hnRNP A1 and FUS suppress these processes through distinct mechanisms. hnRNP A1 inhibits hnRNP K\u2013mediated splicing, and FUS represses the dominant-negative isoform through both its translational inhibition and hnRNP K suppression. Notably, ALS-mutant FUS weakens this regulatory mechanism, leading to impaired repression of hnRNP K and the dominant-negative isoform. Our findings suggest a regulatory network involving ALS-linked RBPs that govern TDP-43 isoform expression and provide new insights into how disruptions in this network contribute to ALS pathogenesis.<\/jats:p>","DOI":"10.1083\/jcb.202406097","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T02:21:08Z","timestamp":1750731668000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Dominant-negative isoform of TDP-43 is regulated by ALS-linked RNA-binding proteins"],"prefix":"10.1083","volume":"224","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9221-1763","authenticated-orcid":true,"given":"Minami","family":"Hasegawa-Ogawa","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/039ygjf22","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medical Sciences, The Jikei University School of Medicine 1 Division of Regenerative Medicine, , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3201-5575","authenticated-orcid":true,"given":"Asako","family":"Onda-Ohto","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/039ygjf22","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medical Sciences, The Jikei University School of Medicine 1 Division of Regenerative Medicine, , Tokyo,","place":["Japan"]},{"id":[{"id":"https:\/\/ror.org\/039ygjf22","id-type":"ROR","asserted-by":"publisher"}],"name":"The Jikei University School of Medicine 2 Department of Neurology, , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2640-3070","authenticated-orcid":true,"given":"Takumasa","family":"Nakajo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/039ygjf22","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medical Sciences, The Jikei University School of Medicine 1 Division of Regenerative Medicine, , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2673-0833","authenticated-orcid":true,"given":"Arisa","family":"Funabashi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/039ygjf22","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medical Sciences, The Jikei University School of Medicine 1 Division of Regenerative Medicine, , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9743-2572","authenticated-orcid":true,"given":"Ayane","family":"Ohya","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/039ygjf22","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medical Sciences, The Jikei University School of Medicine 1 Division of Regenerative Medicine, , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9860-7815","authenticated-orcid":true,"given":"Ryota","family":"Yazaki","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/039ygjf22","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medical Sciences, The Jikei University School of Medicine 1 Division of Regenerative Medicine, , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4611-7098","authenticated-orcid":true,"given":"Hirotaka James","family":"Okano","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/039ygjf22","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medical Sciences, The Jikei University School of Medicine 1 Division of Regenerative Medicine, , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"2025080808545796100_bib1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41467-017-00062-0","article-title":"Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation","volume":"8","author":"Afroz","year":"2017","journal-title":"Nat. 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