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Evidence suggests that mutations in RNA binding proteins (RBPs) such as FUS, a gene associated with ALS, affect the regulation of alternative splicing. We have previously shown that the overexpression of wild-type FUS in mice, a condition that induces ALS-like phenotypes, impacts the splicing of hnRNP A2\/B1, a protein with key roles in RNA metabolism, suggesting that a pathological connection between FUS and hnRNP A2\/B1 might promote FUS-associated toxicity. Here we report that the expression and distribution of different hnRNP A2\/B1 splice variants are modified in the affected tissues of mice overexpressing wild-type FUS. Notably, degenerating motor neurons are characterized by the cytoplasmic accumulation of splice variants of hnRNP A2\/B1 lacking exon 9 (hnRNP A2b\/B1b). In vitro studies show that exon 9 skipping affects the nucleocytoplasmic distribution of hnRNP A2\/B1, promoting its localization into stress granules (SGs), and demonstrate that cytoplasmic localization is the primary driver of hnRNP A2b recruitment into SGs and cell toxicity. Finally, boosting exon 9 skipping using splicing switching oligonucleotides exacerbates disease phenotypes in wild-type FUS mice. Altogether, these findings reveal that alterations of the nucleocytoplasmic distribution of hnRNP A2\/B1, driven by FUS-induced splicing changes, likely contribute to motor neuron degeneration in ALS.<\/jats:p>","DOI":"10.1038\/s41419-025-07538-8","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T22:09:46Z","timestamp":1743286186000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cytoplasmic accumulation of a splice variant of hnRNPA2\/B1 contributes to FUS-associated toxicity in a mouse model of ALS"],"prefix":"10.1038","volume":"16","author":[{"given":"S.","family":"Rossi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Milani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Della Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Bisegna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3293-2607","authenticated-orcid":false,"given":"V.","family":"Durante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Addesse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"D\u2019Avorio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Di Salvio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1142-4752","authenticated-orcid":false,"given":"A.","family":"Serafino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Cestra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5782-1665","authenticated-orcid":false,"given":"S.","family":"Apolloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6646-7653","authenticated-orcid":false,"given":"N.","family":"D\u2019Ambrosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0342-8961","authenticated-orcid":false,"given":"M.","family":"Cozzolino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,29]]},"reference":[{"key":"7538_CR1","doi-asserted-by":"publisher","first-page":"78","DOI":"10.3389\/fnmol.2020.00078","volume":"13","author":"YC Xue","year":"2020","unstructured":"Xue YC, Ng CS, Xiang P, Liu H, Zhang K, Mohamud Y, et al. 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