Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/21853
Title: Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response.
Authors: Johnson, Jennifer L;Stoica, Loredana;Liu, Yuwei;Zhu, Ping Jun;Bhattacharya, Abhisek;Buffington, Shelly;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;Costa-Mattioli, Mauro
Affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA
School of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Murdoch Children's Research Institute, Parkville, VIC 3052, Australia
Department of Audiology and Speech Pathology, University of Melbourne, Melbourne, VIC 3010, Australia
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
The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
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
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
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
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
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA
Murdoch Children's Research Institute, Parkville, VIC 3052, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC 3052, Australia
Hunter Genetics, Hunter New England Local Health District, Newcastle 2298, NSW, Australia
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide 5005, Australia
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
Department of Oncology-Pathology, SciLifeLab, Karolinska Institutet, Solna 17165, Sweden
Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha 34110, Qatar
Oxford Centre for Genomic Medicine, Oxford OX3 7JX, UK
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
Issue Date: 27-Sep-2019
EDate: 2019-10-01
Citation: Neuron 2019; online first: 1 October
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/21853
DOI: 10.1016/j.neuron.2019.08.027
ORCID: 0000-0002-2311-2174
PubMed URL: 31585809
Type: Journal Article
Subjects: autism
immune response
mRNA quality control
memory
neurodevelopmental disorders
speech disorder
Appears in Collections:Journal articles

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