DISC1 regulates N-Methyl-D-Aspartate receptor dynamics: Abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness
| العنوان: | DISC1 regulates N-Methyl-D-Aspartate receptor dynamics: Abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness |
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| المؤلفون: | David J. Porteous, Mostafa Kabiri, Hazel Davidson-Smith, David Price, Marion Bonneau, Daniel L. McCartney, Miles D. Houslay, Paul Perry, J. Kirsty Millar, Kyriakos D. Economides, Shaun Mackie, Laura C. Murphy, Michel Didier, Fumiaki Ogawa, H. Greg Polites, Stephen M. Lawrie, Ellen Grünewald, Barbara Duff, Kathryn L. Evans, Colin A. Semple, Shane T. O’Sullivan, Darragh K. Crummie, Mandy Johnstone, Helen S. Torrance, Jonathan Phillips, Andrew M. McIntosh, Elise L.V. Malavasi, Philippe Gautier, Karen Burr, Costas Constantinides, Susan Anderson, Paraskevi Makedonopoulou, Siddharthan Chandran, Douglas Blackwood, Hannah Murdoch, Matthew Pearson |
| المصدر: | Malavasi, E L V, Economides, K D, Grünewald, E, Makedonopoulou, P, Gautier, P, Mackie, S, Murphy, L C, Murdoch, H, Crummie, D, Ogawa, F, McCartney, D L, O'Sullivan, S T, Burr, K, Torrance, H S, Phillips, J, Bonneau, M, Anderson, S M, Perry, P, Pearson, M, Constantinides, C, Davidson-Smith, H, Kabiri, M, Duff, B, Johnstone, M, Polites, H G, Lawrie, S M, Blackwood, D H, Semple, C A, Evans, K L, Didier, M, Chandran, S, McIntosh, A M, Price, D J, Houslay, M D, Porteous, D J & Millar, J K 2018, ' DISC1 regulates N-methyl-D-aspartate receptor dynamics : abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness ', Translational Psychiatry, vol. 8, no. 1, 184 . https://doi.org/10.1038/s41398-018-0228-1Test Malavasi, E L V, Economides, K D, Grünewald, E, Makedonopoulou, P, Gautier, P, Mackie, S, Murphy, L C, Murdoch, H, Crummie, D, Ogawa, F, McCartney, D L, O’Sullivan, S T, Burr, K, Torrance, H S, Phillips, J, Bonneau, M, Anderson, S M, Perry, P, Pearson, M, Constantinides, C, Davidson-Smith, H, Kabiri, M, Duff, B, Johnstone, M, Polites, H G, Lawrie, S M, Blackwood, D H, Semple, C A, Evans, K L, Didier, M, Chandran, S, McIntosh, A M, Price, D J, Houslay, M D, Porteous, D J & Millar, J K 2018, ' DISC1 regulates N-methyl-D-aspartate receptor dynamics : abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness ', Translational psychiatry, vol. 8, no. 1, 184 . https://doi.org/10.1038/s41398-018-0228-1Test Translational Psychiatry Translational Psychiatry, Vol 8, Iss 1, Pp 1-16 (2018) |
| بيانات النشر: | Cold Spring Harbor Laboratory, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Nerve Tissue Proteins, Chromosomal translocation, medicine.disease_cause, Receptors, N-Methyl-D-Aspartate, Article, Translocation, Genetic, lcsh:RC321-571, Mice, 03 medical and health sciences, DISC1, 0302 clinical medicine, Excitatory synapse, mental disorders, medicine, Animals, Humans, Receptor, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, 030304 developmental biology, Neurons, 0303 health sciences, Mutation, Neuronal Plasticity, biology, Mood Disorders, Sequence Analysis, RNA, 3. Good health, Adaptor Proteins, Vesicular Transport, nervous system, Models, Animal, Synapses, Synaptic plasticity, Schizophrenia, biology.protein, Excitatory postsynaptic potential, NMDA receptor, Carrier Proteins, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study |
| الوصف: | The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-Methyl-D-Aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| DOI: | 10.1101/349365 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::870cbede3d419f12ab6663ee499dc410Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....870cbede3d419f12ab6663ee499dc410 |
| قاعدة البيانات: | OpenAIRE |
| DOI: | 10.1101/349365 |
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