Journal article

Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response

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 Show all

Neuron | CELL PRESS | Published : 2019


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 ..

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Awarded by NIH

Awarded by Intellectual Disability Research Center

Awarded by IDDRC Neuropathology Core (NICHD)

Awarded by BCM Cytometry and Cell Sorting Core

Awarded by Australian NHMRC

Awarded by Australian Research Council

Awarded by NHMRC Centre of Research Excellence

Awarded by NHMRC practitioner fellowship

Awarded by career development fellowship

Awarded by practitioner fellowship

Awarded by senior research fellowship

Funding Acknowledgements

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).