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

Journal article


Johnson, Jennifer L., Stoica, Loredana, Liu, Yuwei, Zhu, Ping Jun, Bhattacharya, Abhisek, Buffington, Shelly A., Huq, Redwan, Eissa, N. Tony, Larsson, Ola, Porse, Bo T., Domingo, Deepti, Nawaz, Urwah, Carroll, Renee, Jolly, Lachlan, Scerri, Tom S., Kim, Hyung-Goo, Brignell, Amanda, Coleman, Matthew J., Braden, Ruth, ... Costa-Mattioli, Mauro. (2019). Inhibition of Upf2-dependent nonsense-mediated decay leads to behavioral and neurophysiological abnormalities by activating the immune response. Neuron. 104(4), pp. 665-679. https://doi.org/10.1016/j.neuron.2019.08.027
AuthorsJohnson, Jennifer L., Stoica, Loredana, Liu, Yuwei, Zhu, Ping Jun, Bhattacharya, Abhisek, Buffington, Shelly A., Huq, Redwan, Eissa, N. Tony, Larsson, Ola, Porse, Bo T., Domingo, Deepti, Nawaz, Urwah, Carroll, Renee, Jolly, Lachlan, Scerri, Tom S., Kim, Hyung-Goo, Brignell, Amanda, Coleman, Matthew J., Braden, Ruth, Kini, Usha, Jackson, Victoria, Baxter, Anne, Bahlo, Melanie, Scheffer, Ingrid E., Amor, David J., Hildebrand, Michael S., Bonnen, Penelope E., Beeton, Christine, Gecz, Jozef, Morgan, Angela T. and Costa-Mattioli, Mauro
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.

KeywordsmRNA quality control; memory; autism; speech disorder; neurodevelopmental disorders; immune response
Year2019
JournalNeuron
Journal citation104 (4), pp. 665-679
PublisherCell Press
ISSN0896-6273
Digital Object Identifier (DOI)https://doi.org/10.1016/j.neuron.2019.08.027
Scopus EID2-s2.0-85074941034
Research or scholarlyResearch
Page range665-679
FunderAustralian Research Council (ARC)
National Health and Medical Research Council (NHMRC)
Publisher's version
License
All rights reserved
File Access Level
Controlled
Output statusPublished
Publication dates
Online01 Oct 2019
Publication process dates
Accepted14 Aug 2019
Deposited11 Jul 2021
ARC Funded ResearchThis output has been funded, wholly or partially, under the Australian Research Council Act 2001
Grant IDARC/DE160100620
NHMRC/1116976
NHMRC/1127144
NHMRC/1105008
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