ArticleNeuron2019
Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response.
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Article in Neuron, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43citing papers in PubMed
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43 citing papers in PubMed, 72 citations in OpenAlex.
- Beyond quality control: biological roles of nonsense-mediated RNA decay.The EMBO journal · 2026Review
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- Nonsense-mediated decay controls a negative feedback loop in innate immune sensing.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Nonsense-mediated mRNA decay and associated splicing patterns in neurodevelopmental disorders.Frontiers in molecular biosciences · 2026Review
- Gene regulation through exon junction complex modularity.Nature structural & molecular biology · 2025Review
- Nonsense-Mediated mRNA Decay: Mechanisms and Recent Implications in Cardiovascular Diseases.Cells · 2025Review
- Biological roles of nonsense-mediated RNA decay: insights from the nervous system.Current opinion in genetics & development · 2025Review
- ESC models of autism with copy-number variations reveal cell-type-specific translational vulnerability.Cell genomics · 2025Article
- Cell type- and factor-specific nonsense-mediated RNA decay.Nucleic acids research · 2025Article
- A Novel UPF1 Variant Associated With a Rare UPF1-Related Neurodevelopmental Disorder.Clinical genetics · 2025Article
- Targeting Tiam1 Enhances Hippocampal-Dependent Learning and Memory in the Adult Brain and Promotes NMDA Receptor-Mediated Synaptic Plasticity and Function.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Messenger RNA Surveillance: Current Understanding, Regulatory Mechanisms, and Future Implications.Molecular biotechnology · 2025Review
- Novel Insights into Changes in Gene Expression within the Hypothalamus in Two Asthma Mouse Models: A Transcriptomic Lung-Brain Axis Study.International journal of molecular sciences · 2024Article
- Effect of nonsense-mediated mRNA decay factor SMG9 deficiency on premature aging in zebrafish.Communications biology · 2024Article
- Genetic architecture of childhood speech disorder: a review.Molecular psychiatry · 2024Review
- Article
- Putting a stop to nonsense: Revisiting gene correction therapy for neurofibromatosis type 1.Molecular therapy. Nucleic acids · 2023Article
- Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells.NAR cancer · 2023Article
- A multi-omic approach identifies an autism spectrum disorder (ASD) regulatory complex of functional epimutations in placentas from children born preterm.Autism research : official journal of the International Society for Autism Research · 2023Article
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Authors and funding
31 authors at 11 institutions in 5 countries.
Jennifer L JohnsonDepartment of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
Loredana StoicaMemory 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.
Yuwei LiuDepartment of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
Ping Jun ZhuDepartment of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
Abhisek BhattacharyaDepartment of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Shelly A BuffingtonDepartment of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
Redwan HuqDepartment of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
N Tony EissaDepartment of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Ola LarssonDepartment of Oncology-Pathology, SciLifeLab, Karolinska Institutet, Solna 17165, Sweden.
Bo T PorseBiotech 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.
Deepti DomingoSchool of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia.
Urwah NawazAdelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide 5005, Australia.
Renee CarrollAdelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide 5005, Australia.
Lachlan JollyAdelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide 5005, Australia.
Tom S ScerriThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Hyung-Goo KimNeurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha 34110, Qatar.
Amanda BrignellMurdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Matthew J ColemanDepartment of Medicine, University of Melbourne, Austin Health, Melbourne, VIC 3010, Australia.
Ruth BradenMurdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Usha KiniOxford Centre for Genomic Medicine, Oxford OX3 7JX, UK.
Victoria JacksonPopulation 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.
Anne BaxterHunter Genetics, Hunter New England Local Health District, Newcastle 2298, NSW, Australia.
Melanie BahloThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3010, Australia.
Ingrid E SchefferMurdoch 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.
David J AmorDepartment of Pediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
Michael S HildebrandDepartment of Medicine, University of Melbourne, Austin Health, Melbourne, VIC 3010, Australia.
Penelope E BonnenDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Christine BeetonDepartment of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Jozef GeczSchool 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.
Angela T MorganMurdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Audiology and Speech Pathology, University of Melbourne, Melbourne, VIC 3010, Australia.
Mauro Costa-MattioliDepartment 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.
Baylor College of Medicine · USThe University of Melbourne · AUThe University of Adelaide · AUMurdoch Children's Research Institute · AUHamad bin Khalifa University · QAHunter Genetics · AURoyal Children's Hospital · AUScience for Life Laboratory · SESouth Australian Health and Medical Research Institute · AUUniversity of Copenhagen · DKWalter and Eliza Hall Institute of Medical Research · AU
Funding
Tumor BiologyP30CA125123 · NCI · BAYLOR COLLEGE OF MEDICINE · PI Michael M Ittmann · 2007 to 2026
$73.9MUNDERSTANDING FXTAS AMONG MALES WITH THE FMR1 PREMUTATIONP30HD024064 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI ROSENMUND, CHRISTIAN · 1988 to 2013
$29.4MVirology CoreP30AI036211 · NIAID · BAYLOR COLLEGE OF MEDICINE · PI BUTEL, JANET S · 1994 to 2015
$21.7MThe integrated stress response in cognitive disordersR01NS076708 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI PFAFFINGER, PAUL, RAY, RUSSELL S · 2012 to 2025
$7.9MMolecular Physiology of the Cardiovascular SystemT32HL007676 · NHLBI · BAYLOR COLLEGE OF MEDICINE · PI HAMILTON, SUSAN L · 1989 to 2020
$7.9MSteps towards a paternal gene activation therapy for Angelman syndromeU54HD083092 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI NELSON, DAVID LOREN, SAMACO, RODNEY C · 2014 to 2019
$7.8MPersonalized Functional Genomics for Mitochondrial Encephalopathy Gene DiscoveryR01NS083726 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI BONNEN, PENELOPE E · 2014 to 2025
$6.1MBD Biosciences Special Order LSRIIS10RR024574 · NCRR · BAYLOR COLLEGE OF MEDICINE · PI LUMPKIN, ELLEN A · 2009 to 2009
$430kNCI NIH HHS P30 CA125123NCRR NIH HHS S10 RR024574NHLBI NIH HHS T32 HL007676NIAID NIH HHS P30 AI036211NICHD NIH HHS P30 HD024064NICHD NIH HHS U54 HD083092NINDS NIH HHS R01 NS076708NINDS NIH HHS R01 NS083726
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.
Indexed as
AnimalsChildDrosophilaFemaleHumansLanguage Development DisordersLearningMaleMemoryMiceMice, KnockoutNonsense Mediated mRNA DecayRNA-Binding ProteinsRNA-Binding ProteinsUPF2 protein, humanUpf2 protein, mouseautismimmune responsememorymRNA quality controlneurodevelopmental disordersspeech disorder
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