Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/122742
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dc.contributor.authorJohnson, J.L.en
dc.contributor.authorStoica, L.en
dc.contributor.authorLiu, Y.en
dc.contributor.authorZhu, P.J.en
dc.contributor.authorBhattacharya, A.en
dc.contributor.authorBuffington, S.en
dc.contributor.authorHuq, R.en
dc.contributor.authorEissa, N.T.en
dc.contributor.authorLarsson, O.en
dc.contributor.authorPorse, B.T.en
dc.contributor.authorDomingo, D.en
dc.contributor.authorNawaz, U.en
dc.contributor.authorCarroll, R.en
dc.contributor.authorJolly, L.en
dc.contributor.authorScerri, T.S.en
dc.contributor.authorKim, H.-.G.en
dc.contributor.authorBrignell, A.en
dc.contributor.authorColeman, M.J.en
dc.contributor.authorBraden, R.en
dc.contributor.authorKini, U.en
dc.contributor.authoret al.en
dc.date.issued2019en
dc.identifier.citationNeuron, 2019; 104(4):665-679.e8en
dc.identifier.issn0896-6273en
dc.identifier.issn1097-4199en
dc.identifier.urihttp://hdl.handle.net/2440/122742-
dc.description.abstractIn humans, disruption of nonsense-mediated decay (NMD) has been associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability. However, the mechanism by which deficient NMD leads to neurodevelopmental dysfunction remains unknown, preventing development of targeted therapies. Here we identified novel protein-coding UPF2 (UP-Frameshift 2) variants in humans with NDD, including speech and language deficits. In parallel, we found that mice lacking Upf2 in the forebrain (Upf2 fb-KO mice) show impaired NMD, memory deficits, abnormal long-term potentiation (LTP), and social and communication deficits. Surprisingly, Upf2 fb-KO mice exhibit elevated expression of immune genes and brain inflammation. More importantly, treatment with two FDA-approved anti-inflammatory drugs reduced brain inflammation, restored LTP and long-term memory, and reversed social and communication deficits. Collectively, our findings indicate that impaired UPF2-dependent NMD leads to neurodevelopmental dysfunction and suggest that anti-inflammatory agents may prove effective for treatment of disorders with impaired NMD.en
dc.description.statementofresponsibilityJennifer L. Johnson, Loredana Stoica, Yuwei Liu, Ping Jun Zhu, Abhisek Bhattacharya, Shelly A. Buffington, Redwan Huq, N. Tony Eissa, Ola Larsson, Bo T. Porse, Deepti Domingo, Urwah Nawaz, Renee Carroll, Lachlan Jolly, Tom S. Scerri, Hyung-Goo Kim, Amanda Brignell, Matthew J. Coleman, Ruth Braden, Usha Kini, Victoria Jackson, Anne Baxter, Melanie Bahlo, Ingrid E. Scheffer, David J. Amor, Michael S. Hildebrand, Penelope E. Bonnen, Christine Beeton, Jozef Gecz, Angela T. Morgan, and Mauro Costa-Mattiolien
dc.language.isoenen
dc.publisherElsevieren
dc.rights© 2019 Published by Elsevier Inc.en
dc.subjectmRNA quality control; memory; autism; speech disorder; neurodevelopmental disorders; immune responseen
dc.titleInhibition of Upf2-dependent nonsense-mediated decay leads to behavioral and neurophysiological abnormalities by activating the immune responseen
dc.typeJournal articleen
dc.identifier.rmid1000001379en
dc.identifier.doi10.1016/j.neuron.2019.08.027en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1155224en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1091593en
dc.relation.granthttp://purl.org/au-research/grants/arc/DE160100620en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1116976en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1127144en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1105008en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1063799en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1006110en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1102971en
dc.identifier.pubid499525-
pubs.library.collectionMedicine publicationsen
pubs.library.teamDS14en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidCarroll, R. [0000-0002-6979-3710]en
dc.identifier.orcidJolly, L. [0000-0003-4538-2658]en
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]en
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