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
Authors | 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, 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 |
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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 |
Year | 2019 |
Journal | Neuron |
Journal citation | 104 (4), pp. 665-679 |
Publisher | Cell Press |
ISSN | 0896-6273 |
Digital Object Identifier (DOI) | https://doi.org/10.1016/j.neuron.2019.08.027 |
Scopus EID | 2-s2.0-85074941034 |
Research or scholarly | Research |
Page range | 665-679 |
Funder | Australian Research Council (ARC) |
National Health and Medical Research Council (NHMRC) | |
Publisher's version | License All rights reserved File Access Level Controlled |
Output status | Published |
Publication dates | |
Online | 01 Oct 2019 |
Publication process dates | |
Accepted | 14 Aug 2019 |
Deposited | 11 Jul 2021 |
ARC Funded Research | This output has been funded, wholly or partially, under the Australian Research Council Act 2001 |
Grant ID | ARC/DE160100620 |
NHMRC/1116976 | |
NHMRC/1127144 | |
NHMRC/1105008 |
https://acuresearchbank.acu.edu.au/item/8w583/inhibition-of-upf2-dependent-nonsense-mediated-decay-leads-to-behavioral-and-neurophysiological-abnormalities-by-activating-the-immune-response
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