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Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia
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Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia
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Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia
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Journal Article
Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia
2015
Overview
The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders, and schizophrenia specifically. We enriched for this anatomical structure, in the anterior cingulate cortex, of 20 schizophrenia samples and 20 controls from the Stanley Medical Research Institute, and used unbiased shotgun proteomics incorporating label-free quantitation to identify differentially expressed proteins. Quantitative investigation of the PSD revealed more than 700 protein identifications and 143 differentially expressed proteins. Prominent among these were altered expression of proteins involved in clathrin-mediated endocytosis (CME) (Dynamin-1, adaptor protein 2) and
N
-methyl-D-aspartate (NMDA)-interacting proteins such as CYFIP2, SYNPO, SHANK3, ESYT and MAPK3 (all
P
<0.0015). Pathway analysis of the differentially expressed proteins implicated the cellular processes of endocytosis, long-term potentiation and calcium signaling. Both single-gene and gene-set enrichment analyses in genome-wide association data from the largest schizophrenia sample to date of 13 689 cases and 18 226 controls show significant association of
HIST1H1E
and
MAPK3
, and enrichment of our PSD proteome. Taken together, our data provide robust evidence implicating PSD-associated proteins and genes in schizophrenia, and suggest that within the PSD, NMDA-interacting and endocytosis-related proteins contribute to disease pathophysiology.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/43
/ 64/86
/ 82/58
/ Animals
/ Antipsychotic Agents - pharmacology
/ Clathrin
/ Dynamin
/ Female
/ Gene Expression Regulation - genetics
/ Genomes
/ Genomics
/ Gyrus Cinguli - drug effects
/ Humans
/ Male
/ Medicine
/ N-Methylaspartate - genetics
/ N-Methylaspartate - metabolism
/ Nerve Tissue Proteins - genetics
/ Nerve Tissue Proteins - metabolism
/ Post-Synaptic Density - genetics
/ Post-Synaptic Density - metabolism
/ Post-Synaptic Density - pathology
/ Proteins
/ Rats
/ Signal Transduction - drug effects
/ Signal Transduction - physiology
/ Synapses
