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Neuron. 2019 Oct 1. pii: S0896-6273(19)30733-0. doi: 10.1016/j.neuron.2019.08.027. [Epub ahead of print]

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

Author information

1
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
2
Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Oncology-Pathology, SciLifeLab, Karolinska Institutet, Solna 17165, Sweden.
6
Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen 1165, Denmark; The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen 1165, Denmark; Danish Stem Cell Centre (DanStem), Faculty of Health Sciences, University of Copenhagen, Copenhagen 1165, Denmark.
7
School of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia.
8
Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide 5005, Australia.
9
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
10
Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha 34110, Qatar.
11
Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
12
Department of Medicine, University of Melbourne, Austin Health, Melbourne, VIC 3010, Australia.
13
Oxford Centre for Genomic Medicine, Oxford OX3 7JX, UK.
14
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Melbourne, VIC 3010, Australia; Department of Medical Biology and School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3010, Australia.
15
Hunter Genetics, Hunter New England Local Health District, Newcastle 2298, NSW, Australia.
16
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3010, Australia.
17
Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Medicine, University of Melbourne, Austin Health, Melbourne, VIC 3010, Australia; Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia.
18
Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
19
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
20
School of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia; Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide 5005, Australia; Healthy Mothers and Babies, South Australian Health and Medical Research Institute, Adelaide 5000, Australia.
21
Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Audiology and Speech Pathology, University of Melbourne, Melbourne, VIC 3010, Australia.
22
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: costamat@bcm.edu.

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:

autism; immune response; mRNA quality control; memory; neurodevelopmental disorders; speech disorder

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