Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response
| العنوان: | Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response |
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| المؤلفون: | Ingrid E. Scheffer, Jennifer L. Johnson, Hyung-Goo Kim, Michael S. Hildebrand, Ping Jun Zhu, Penelope E. Bonnen, Amanda Brignell, Christine Beeton, Victoria E. Jackson, Abhisek Bhattacharya, N. Tony Eissa, Urwah Nawaz, Yuwei Liu, Redwan Huq, Thomas S. Scerri, Loredana Stoica, Melanie Bahlo, Bo T. Porse, Renee Carroll, Jozef Gecz, Matthew Coleman, Usha Kini, Deepti Domingo, Ola Larsson, Anne Baxter, David J. Amor, Lachlan A. Jolly, Shelly A. Buffington, Mauro Costa-Mattioli, Ruth O Braden, Angela T Morgan |
| المصدر: | Johnson, J L, Stoica, L, Liu, Y, Zhu, P J, Bhattacharya, A, Buffington, S, Huq, R, Eissa, N T, Larsson, O, Porse, B T, Domingo, D, Nawaz, U, Carroll, R, Jolly, L, Scerri, T S, Kim, H-G, Brignell, A, Coleman, M J, Braden, R, Kini, U, Jackson, V, Baxter, A, Bahlo, M, Scheffer, I E, Amor, D J, Hildebrand, M S, Bonnen, P E, Beeton, C, Gecz, J, Morgan, A T & Costa-Mattioli, M 2019, ' Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response ', Neuron, vol. 104, no. 4, pp. 665-679 . https://doi.org/10.1016/j.neuron.2019.08.027 Neuron |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Nonsense-mediated decay, autism, Inflammation, speech disorder, immune response, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Research Support, N.I.H., Extramural, Memory, Intellectual disability, medicine, Journal Article, Animals, Humans, Learning, Language Development Disorders, RNA, Messenger, Child, Mice, Knockout, mRNA quality control, business.industry, General Neuroscience, Research Support, Non-U.S. Gov't, RNA-Binding Proteins, Long-term potentiation, medicine.disease, 3. Good health, Nonsense Mediated mRNA Decay, 030104 developmental biology, Phenotype, Autism spectrum disorder, Neurodevelopmental Disorders, Synaptic plasticity, Forebrain, Autism, Drosophila, Female, medicine.symptom, business, Carrier Proteins, Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1097-4199 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ad35e7f7e3352d68951cef438e476e08 https://pubmed.ncbi.nlm.nih.gov/31751540 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ad35e7f7e3352d68951cef438e476e08 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10974199 |
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