| Abstract |
The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders, and精神分裂症specifically. We enriched for this anatomical structure, in the anterior cingulate cortex, of 20精神分裂症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精神分裂症sample to date of 13,689 cases and 18,226 controls show significant association ofHIST1H1Eand MAPK3, and enrichment of our PSD proteome. Taken together, our data provide robust evidence implicating PSD-associated proteins and genes in精神分裂症, and suggest that within the PSD, NMDA-interacting and endocytosis-related proteins contribute to disease pathophysiology. |