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Interaction of p53 and its signaling network with RNA-binding proteins (RBPs) helps fine-tune its activation and the resulting cell fates. Preclinical therapeutics based on depletion of the RBP STAUFEN-1 (STAU1) protein successfully prevent neurodegeneration, however, the specific mechanisms are not fully understood. STAU1 is pathologically overabundant in multiple neurological disorders and contributes to neurodegeneration by exacerbating autophagy dysfunction, endoplasmic reticulum stress, and RNA-protein condensate accumulation. We previously showed that lowering STAU1 levels mitigates these disease-related features and prevents neuronal death in animal models of amyotrophic lateral sclerosis\/frontotemporal dementia (ALS\/FTD) and spinocerebellar ataxia type 2 (SCA2). Here, we show by combined transcriptomic and functional analyses that STAU1 reduction results in the inhibition of apoptosis through the p53 pathway. In both proliferating and post-mitotic cell types\u2014human iPSC-derived neurons, mouse cortical neurons, SH-SY5Y cells, and fibroblasts\u2014STAU1 reduction effectively prevented p53-mediated apoptosis and DNA damage induced by Nutlin-3 and etoposide. Further examination in C9orf72-expanded patient-derived fibroblasts and a C9orf72 mouse model of ALS\/FTD, which exhibit baseline overabundance of STAU1 and activation of the p53 pathway, confirmed that STAU1 reduction also prevented p53-driven pro-apoptotic signaling. These findings establish STAU1 as a novel modulator of DNA damage and p53-dependent apoptosis, suggesting that targeting STAU1 could be a promising approach to prevent neurodegeneration in ALS\/FTD.<\/jats:p>","DOI":"10.1038\/s41419-025-08067-0","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T16:13:11Z","timestamp":1761581591000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting STAU1 prevents p53 apoptotic signaling in neurodegeneration"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2697-0390","authenticated-orcid":false,"given":"Mandi","family":"Gandelman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharan","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla P.","family":"Figueroa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Sundrud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warunee","family":"Dansithong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3271-9912","authenticated-orcid":false,"given":"Daniel R.","family":"Scoles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0883-7879","authenticated-orcid":false,"given":"Stefan M.","family":"Pulst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"8067_CR1","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1186\/s13195-020-00732-0","volume":"12","author":"G Abate","year":"2020","unstructured":"Abate G, Frisoni GB, Bourdon JC, Piccirella S, Memo M, Uberti D. 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