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 A.
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 - Funding Information:
We thank the individuals carrying UPF variants and their families for participating in our research program. We thank members of the Costa-Mattioli laboratory for comments on the manuscript. This work was supported by the NIH ( NIMH 096816 and NINDS 076708 to M.C.M.); Sammons Enterprises (to M.C.M.); the Intellectual Disability Research Center ( P30HD024064 ), IDDRC Neuropathology Core ( NICHD , U54HD083092 ), BCM Cytometry and Cell Sorting Core ( RR024574 , AI036211 , and CA125123 ), and T32 award HL007676 from the NIH (to R.H.); a centre grant from the Novo Nordisk Foundation (to B.P.); and the Australian State of Victoria Government Operational Infrastructure Support Program and the Australian National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme (IRIISS). J.G. was supported by Australian NHMRC grants 1155224 and 1091593 . L.J. was supported by Australian Research Council fellowship DE160100620 . A.M., M.H., D.A., I.E.S., and M.B. are funded by NHMRC Centre of Research Excellence ( 1116976 ) and project ( 1127144 ) grants. A.M. is funded by an NHMRC practitioner fellowship ( 1105008 ). M.H. is funded by a career development fellowship (ID 1063799 ). I.E.S. is funded by a practitioner fellowship ( 1006110 ). M.B. is funded by a senior research fellowship (ID 1102971 ).
Publisher Copyright:
© 2019
PY - 2019/11/20
Y1 - 2019/11/20
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.
KW - autism
KW - immune response
KW - mRNA quality control
KW - memory
KW - neurodevelopmental disorders
KW - speech disorder
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U2 - 10.1016/j.neuron.2019.08.027
DO - 10.1016/j.neuron.2019.08.027
M3 - Article
C2 - 31585809
AN - SCOPUS:85074941034
SN - 0896-6273
VL - 104
SP - 665-679.e8
JO - Neuron
JF - Neuron
IS - 4
ER -