Inhibition of Upf2-dependent nonsense-mediated decay leads to behavioral and neurophysiological abnormalities by activating the immune response

Simple item page
dc.contributor.authorJohnson, J.L.
dc.contributor.authorStoica, L.
dc.contributor.authorLiu, Y.
dc.contributor.authorZhu, P.J.
dc.contributor.authorBhattacharya, A.
dc.contributor.authorBuffington, S.
dc.contributor.authorHuq, R.
dc.contributor.authorEissa, N.T.
dc.contributor.authorLarsson, O.
dc.contributor.authorPorse, B.T.
dc.contributor.authorDomingo, D.
dc.contributor.authorNawaz, U.
dc.contributor.authorCarroll, R.
dc.contributor.authorJolly, L.
dc.contributor.authorScerri, T.S.
dc.contributor.authorKim, H.-G.
dc.contributor.authorBrignell, A.
dc.contributor.authorColeman, M.J.
dc.contributor.authorBraden, R.
dc.contributor.authorKini, U.
dc.contributor.authoret al.
dc.date.issued2019
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.
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-Mattioli
dc.identifier.citationNeuron, 2019; 104(4):665-679.e8
dc.identifier.doi10.1016/j.neuron.2019.08.027
dc.identifier.issn0896-6273
dc.identifier.issn1097-4199
dc.identifier.orcidNawaz, U. [0000-0002-3703-4445]
dc.identifier.orcidCarroll, R. [0000-0002-6979-3710]
dc.identifier.orcidJolly, L. [0000-0003-4538-2658]
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttp://hdl.handle.net/2440/122742
dc.language.isoen
dc.publisherElsevier
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1155224
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1091593
dc.relation.granthttp://purl.org/au-research/grants/arc/DE160100620
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1116976
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1127144
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1105008
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1063799
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1006110
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1102971
dc.rights© 2019 Published by Elsevier Inc.
dc.source.urihttps://doi.org/10.1016/j.neuron.2019.08.027
dc.subjectmRNA quality control; memory; autism; speech disorder; neurodevelopmental disorders; immune response
dc.titleInhibition of Upf2-dependent nonsense-mediated decay leads to behavioral and neurophysiological abnormalities by activating the immune response
dc.typeJournal article
pubs.publication-statusPublished

Files

Collections

Medicine publications