TY - JOUR
T1 - Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response
AU - Johnson, Jennifer L
AU - Stoica, Loredana
AU - Liu, Yuwei
AU - Zhu, Ping Jun
AU - Bhattacharya, Abhisek
AU - Buffington, Shelly
AU - Huq, Redwan
AU - Eissa, N Tony
AU - Larsson, Ola
AU - Porse, Bo T
AU - Domingo, Deepti
AU - Nawaz, Urwah
AU - Carroll, Renee
AU - Jolly, Lachlan
AU - Scerri, Tom S
AU - Kim, Hyung-Goo
AU - Brignell, Amanda
AU - Coleman, Matthew J
AU - Braden, Ruth
AU - Kini, Usha
AU - Jackson, Victoria
AU - Baxter, Anne
AU - Bahlo, Melanie
AU - Scheffer, Ingrid E
AU - Amor, David J
AU - Hildebrand, Michael S
AU - Bonnen, Penelope E
AU - Beeton, Christine
AU - Gecz, Jozef
AU - Morgan, Angela T
AU - Costa-Mattioli, Mauro
N1 - Copyright © 2019. Published by Elsevier Inc.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.1016/j.neuron.2019.08.027
DO - 10.1016/j.neuron.2019.08.027
M3 - Journal article
C2 - 31585809
VL - 104
SP - 665
EP - 679
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 4
ER -