{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T19:54:22Z","timestamp":1778788462152,"version":"3.51.4"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T00:00:00Z","timestamp":1678320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG064069"],"award-info":[{"award-number":["AG064069"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG047339"],"award-info":[{"award-number":["AG047339"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1TR002345"],"award-info":[{"award-number":["UL1TR002345"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bluefield Project to Cure FTD"},{"DOI":"10.13039\/100013669","name":"Ionis Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013669","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013669","name":"Ionis Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013669","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013669","name":"Ionis Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013669","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>A common cause of frontotemporal dementia (FTD) are nonsense mutations in the progranulin <jats:italic>(GRN)<\/jats:italic> gene. Because nonsense mutations activate the nonsense-mediated RNA decay (NMD) pathway, we sought to inhibit this RNA turnover pathway as a means to increase progranulin levels. Using a knock-in mouse model harboring a common patient mutation, we tested whether either pharmacological or genetic inhibition of NMD upregulates progranulin in these <jats:italic>Grn<\/jats:italic><jats:sup><jats:italic>R493X<\/jats:italic><\/jats:sup> mice. We first examined antisense oligonucleotides (ASOs) targeting an exonic region in <jats:italic>Grn<\/jats:italic><jats:sup><jats:italic>R493X<\/jats:italic><\/jats:sup> mRNA predicted to block its degradation by NMD. As we previously reported, these ASOs effectively increased <jats:italic>Grn<\/jats:italic><jats:sup><jats:italic>R493X<\/jats:italic><\/jats:sup> mRNA levels in fibroblasts <jats:italic>in vitro<\/jats:italic>. However, following CNS delivery, we found that none of the 8 ASOs we tested increased <jats:italic>Grn<\/jats:italic> mRNA levels in the brains of <jats:italic>Grn<\/jats:italic><jats:sup><jats:italic>R493X<\/jats:italic><\/jats:sup> mice. This result was obtained despite broad ASO distribution in the brain. An ASO targeting a different mRNA was effective when administered in parallel to wild-type mice. As an independent approach to inhibit NMD, we examined the effect of loss of an NMD factor not required for embryonic viability: UPF3b. We found that while <jats:italic>Upf3b<\/jats:italic> deletion effectively perturbed NMD, it did not increase <jats:italic>Grn<\/jats:italic> mRNA levels in <jats:italic>Grn<\/jats:italic><jats:sup><jats:italic>+\/R493X<\/jats:italic><\/jats:sup> mouse brains. Together, our results suggest that the NMD-inhibition approaches that we used are likely not viable for increasing progranulin levels in individuals with FTD caused by nonsense <jats:italic>GRN<\/jats:italic> mutations. Thus, alternative approaches should be pursued.<\/jats:p>","DOI":"10.1371\/journal.pone.0282822","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T18:45:56Z","timestamp":1678387556000},"page":"e0282822","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting nonsense-mediated RNA decay does not increase progranulin levels in the Grn R493X mouse model of frontotemporal dementia"],"prefix":"10.1371","volume":"18","author":[{"given":"Denise M.","family":"Smith","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael 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to chromosome 17q21","volume":"442","author":"M Cruts","year":"2006","journal-title":"Nature"},{"issue":"7105","key":"pone.0282822.ref004","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/nature05016","article-title":"Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17","volume":"442","author":"M Baker","year":"2006","journal-title":"Nature"},{"key":"pone.0282822.ref005","doi-asserted-by":"crossref","first-page":"713031","DOI":"10.3389\/fnmol.2021.713031","article-title":"Tweaking progranulin expression: therapeutic avenues and opportunities","volume":"14","author":"J Terryn","year":"2021","journal-title":"Front Mol Neurosci"},{"key":"pone.0282822.ref006","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.conb.2021.10.001","article-title":"New insights and therapeutic opportunities for progranulin-deficient frontotemporal dementia","volume":"72","author":"S Amin","year":"2021","journal-title":"Curr Opin 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