{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:56:40Z","timestamp":1790596600045,"version":"4.1.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the cytoplasmic mislocalization, aberrant phosphorylation and pathological aggregation of TDP-43, a nuclear RNA-binding protein essential for RNA metabolism. Despite its central involvement in ALS pathogenesis, the molecular mechanisms that govern TDP-43 proteostasis remain incompletely understood. Here, we investigated the role of LRSAM1, an E3 ubiquitin ligase, in regulating TDP-43 localization and degradation.<\/jats:p>\n                  <jats:p>Postmortem spinal cord tissues from five patients with sporadic amyotrophic lateral sclerosis and five healthy controls were examined. Immunohistochemical analyses revealed that LRSAM1 preferentially colocalized with diffusely mislocalized cytoplasmic TDP-43 but not with dense cytoplasmic aggregates, suggesting a potential role in early-stage pathological processing. To model these effects in vitro, induced pluripotent stem cell-derived motor neurons from three patients with amyotrophic lateral sclerosis and four healthy control participants were used. Knockdown of LRSAM1 in induced pluripotent stem cell-derived motor neurons from patients with amyotrophic lateral sclerosis significantly increased cytoplasmic TDP-43 accumulation and phosphorylation, as measured by immunofluorescence imaging. Moreover, STMN2 mRNA splicing, a well-established TDP-43 functional readout, was disrupted upon LRSAM1 depletion. Conversely, overexpression of LRSAM1 ameliorated stress-induced TDP-43 mislocalization and phosphorylation in induced pluripotent stem cell-derived motor neurons from patients with amyotrophic lateral sclerosis but had minimal impact in control cells, indicating disease-specific vulnerability. Mechanistically, LRSAM1 interacted directly with the aggregation-prone C-terminal fragments of TDP-43 via the RRM2 domain of TDP-43 and promoted their proteasomal degradation. This selective interaction reduced the accumulation of toxic TDP-43 species and supported cytoplasmic proteostasis, particularly under conditions of cellular stress.<\/jats:p>\n                  <jats:p>In summary, our study identifies LRSAM1 as a novel modulator of cytoplasmic TDP-43 dynamics in amyotrophic lateral sclerosis. By facilitating degradation of pathogenic TDP-43 fragments, LRSAM1 preserves neuronal RNA processing and mitigates molecular hallmarks of amyotrophic lateral sclerosis. These findings enhance our understanding of post-translational control of TDP-43 and highlight LRSAM1 as a promising therapeutic target for modifying disease progression in amyotrophic lateral sclerosis.<\/jats:p>","DOI":"10.1093\/brain\/awag334","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:22:26Z","timestamp":1790425346000},"source":"Crossref","is-referenced-by-count":0,"title":["LRSAM1, an E3 ubiquitin ligase, modulates TDP-43 proteostasis in amyotrophic lateral sclerosis"],"prefix":"10.1093","author":[{"given":"Takayuki","family":"Shirakawa","sequence":"first","affiliation":[{"name":"NeuroDiscovery Lab, Tanabe Pharma America , Boston, MA 02135 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satsuki","family":"Mikuriya","sequence":"additional","affiliation":[{"name":"NeuroDiscovery Lab, Tanabe Pharma America , Boston, MA 02135 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Inoue","sequence":"additional","affiliation":[{"name":"Discovery Technology Laboratories, Sohyaku. Innovative Research Division, Tanabe Pharma Corporation , Fujisawa, Kanagawa 251-8555 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Murasaki","sequence":"additional","affiliation":[{"name":"Discovery Technology Laboratories, Sohyaku. Innovative Research Division, Tanabe Pharma Corporation , Yokohama, Kanagawa 227-0033 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florencia","family":"Salinas","sequence":"additional","affiliation":[{"name":"NeuroDiscovery Lab, Tanabe Pharma America , Boston, MA 02135 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomo","family":"Takegawa-Araki","sequence":"additional","affiliation":[{"name":"NeuroDiscovery Lab, Tanabe Pharma America , Boston, MA 02135 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7034-8094","authenticated-orcid":false,"given":"Makoto","family":"Tamura","sequence":"additional","affiliation":[{"name":"NeuroDiscovery Lab, Tanabe Pharma America , Boston, MA 02135 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,28]]},"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag334\/71437615\/awag334.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag334\/71437615\/awag334.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:11:03Z","timestamp":1790593863000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/advance-article\/doi\/10.1093\/brain\/awag334\/8841148"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/brain\/awag334","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]},"article-number":"awag334"}}