Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/122742
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Type: Journal article
Title: Inhibition of Upf2-dependent nonsense-mediated decay leads to behavioral and neurophysiological abnormalities by activating the immune response
Author: Johnson, J.L.
Stoica, L.
Liu, Y.
Zhu, P.J.
Bhattacharya, A.
Buffington, S.
Huq, R.
Eissa, N.T.
Larsson, O.
Porse, B.T.
Domingo, D.
Nawaz, U.
Carroll, R.
Jolly, L.
Scerri, T.S.
Kim, H.-.G.
Brignell, A.
Coleman, M.J.
Braden, R.
Kini, U.
et al.
Citation: Neuron, 2019; 104(4):665-679.e8
Publisher: Elsevier
Issue Date: 2019
ISSN: 0896-6273
1097-4199
Statement of
Responsibility: 
Jennifer 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
Abstract: In 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.
Keywords: mRNA quality control; memory; autism; speech disorder; neurodevelopmental disorders; immune response
Rights: © 2019 Published by Elsevier Inc.
RMID: 1000001379
DOI: 10.1016/j.neuron.2019.08.027
Grant ID: http://purl.org/au-research/grants/nhmrc/1155224
http://purl.org/au-research/grants/nhmrc/1091593
http://purl.org/au-research/grants/arc/DE160100620
http://purl.org/au-research/grants/nhmrc/1116976
http://purl.org/au-research/grants/nhmrc/1127144
http://purl.org/au-research/grants/nhmrc/1105008
http://purl.org/au-research/grants/nhmrc/1063799
http://purl.org/au-research/grants/nhmrc/1006110
http://purl.org/au-research/grants/nhmrc/1102971
Appears in Collections:Medicine publications

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