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Increasing the expression of the cold\u2010shock protein RBM3 through therapeutic hypothermia is remarkably neuroprotective. However, systemic cooling poses a health risk, strongly limiting its clinical application. Selective upregulation of RBM3 at normothermia thus holds immense therapeutic potential. Here we identify a poison exon within the RBM3 gene that is solely responsible for its cold\u2010induced expression. Genetic removal or antisense oligonucleotide (ASO)\u2010mediated manipulation of this exon yields high RBM3 levels independent of cooling. Notably, a single administration of ASO to exclude the poison exon, using FDA\u2010approved chemistry, results in long\u2010lasting increased RBM3 expression in mouse brains. In prion\u2010diseased mice, this treatment leads to remarkable neuroprotection, with prevention of neuronal loss and spongiosis despite high levels of disease\u2010associated prion protein. Our promising results in mice support the possibility that RBM3\u2010inducing ASOs might also deliver neuroprotection in humans in conditions ranging from acute brain injury to Alzheimer's disease.<\/jats:p>","DOI":"10.15252\/emmm.202217157","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T07:00:27Z","timestamp":1679468427000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["ASO targeting RBM3 temperature\u2010controlled poison exon splicing prevents neurodegeneration in vivo"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5155-0844","authenticated-orcid":false,"given":"Marco","family":"Preu\u00dfner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9706-5163","authenticated-orcid":false,"given":"Daniel","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann\u2010Kathrin","family":"Emmerichs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Scalzitti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Peretti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Swinden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Haltenhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8504-1191","authenticated-orcid":false,"given":"Giovanna R","family":"Mallucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9377-9882","authenticated-orcid":false,"given":"Florian","family":"Heyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,22]]},"reference":[{"key":"BFEMMM202217157_CR1","doi-asserted-by":"crossref","DOI":"10.3390\/jcm11040949","volume":"11","author":"P \u00c1vila\u2010G\u00f3mez","year":"2022","unstructured":"\u00c1vila\u2010G\u00f3mez P, P\u00e9rez\u2010Mato M, Hervella P, Dopico\u2010L\u00f3pez A, Silva\u2010Candal AD, Bugallo\u2010Casal A, L\u00f3pez\u2010Amoedo S, Candamo\u2010Lourido M, Sobrino T, Iglesias\u2010Rey R et\u00a0al (2022) Associations between RNA\u2010binding motif protein 3, fibroblast growth factor 21, and clinical outcome in patients with stroke. 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