Comprehensive post mortem brain samples analysis detects global reduction of multiple proteasome subunits expression in schizophrenia

Background: Ubiquitination is a common post-translational modification, responsible for proteasomal degradation, the main intracellular protein degradation system. Recently, aggregations of ubiquitinated proteins have been identified in schizophrenia. While disruption of proteasome activity is a potential cause, search for such disruption in schizophrenia has yielded inconsistent results. Methods: We performed transcriptome sequencing of 14 postmortem superior temporal gyrus (STG) samples of subjects with schizophrenia and 15 matched controls from the Stanley Medical Research Institute (SMRI), and compared differential expression (schizophrenia vs. control) and pathway enrichment analysis to that of an independent cohort from the Mount Sinai School of Medicine (MSSM). Meta-analysis of differential expression was applied to 39 proteasome subunits genes. Replicability was tested on six additional independent datasets of four additional brain regions. Results: The two independent STG cohorts showed high replicability. Pathway enrichment analysis of the schizophrenia down-regulated genes pointed to proteasome-related pathways. 12 out of 39 proteasome subunit genes were found to be down-regulated in schizophrenia. The signal of down-regulation of multiple proteasome subunits in schizophrenia was replicated in six additional datasets. Conclusions: We detect global down-regulation of multiple proteasome subunits in schizophrenia. The concordance between 8 independent cohorts (overall 267 schizophrenia and 266 control samples) remarkably strengthens the validity and robustness of our results. The observed down-regulation might lead to proteasome dysfunction that can be the cause of the recently detected aggregation of ubiquitinated proteins in schizophrenia.