DISC1 regulates N-methyl-D-aspartate receptor dynamics: abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness.

Autor: Malavasi ELV; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Economides KD; Xtuit Pharmaceuticals, Waltham, MA, USA., Grünewald E; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Makedonopoulou P; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Gautier P; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Mackie S; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Murphy LC; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Murdoch H; Molecular Pharmacology Group, Wolfson Building, Institute of Neuroscience and Psychology, The University of Glasgow, University Avenue, Glasgow, UK., Crummie D; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Ogawa F; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., McCartney DL; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., O'Sullivan ST; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Burr K; Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK., Torrance HS; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Phillips J; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Bonneau M; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Anderson SM; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Perry P; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Pearson M; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Constantinides C; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Davidson-Smith H; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Kabiri M; Translational In Vivo Models at Sanofi, Frankfurt, Germany., Duff B; Division of Psychiatry, The University of Edinburgh, Edinburgh, UK., Johnstone M; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK.; Division of Psychiatry, The University of Edinburgh, Edinburgh, UK., Polites HG; Regeneron Pharmaceuticals, Tarrytown NY, USA., Lawrie SM; Division of Psychiatry, The University of Edinburgh, Edinburgh, UK., Blackwood DH; Division of Psychiatry, The University of Edinburgh, Edinburgh, UK., Semple CA; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Evans KL; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Didier M; Translational Sciences at Sanofi, Chilly-Mazarin, France., Chandran S; Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK., McIntosh AM; Division of Psychiatry, The University of Edinburgh, Edinburgh, UK., Price DJ; Centre for Integrative Physiology, The University of Edinburgh, Edinburgh, UK., Houslay MD; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK., Porteous DJ; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK., Millar JK; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK. kirsty.millar@igmm.ed.ac.uk.
Jazyk: angličtina
Zdroj: Translational psychiatry [Transl Psychiatry] 2018 Sep 06; Vol. 8 (1), pp. 184. Date of Electronic Publication: 2018 Sep 06.
DOI: 10.1038/s41398-018-0228-1
Abstrakt: 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 the 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.
Databáze: MEDLINE
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