ABSTRACT
Background Ubiquitination of proteins is responsible for proteasomal degradation, the main intracellular protein degradation system. Recently, aggregations of ubiquitinated proteins have been identified in schizophrenia. While proteasome activity disruption is a potential cause, previous studies have yielded inconsistent results.
Methods We performed transcriptome sequencing of 14 superior temporal gyrus (STG) samples of subjects with schizophrenia and 15 matched controls from the Stanley Medical Research Institute (SMRI), and compared differential expression and pathway enrichment analysis to that of an independent cohort. 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 STG cohorts showed high replicability. Pathway enrichment analysis of the down-regulated genes pointed to proteasome-related pathways. 12 of 39 proteasome subunit genes were found to be down-regulated in schizophrenia. The signal of down-regulation of multiple proteasome subunits was replicated in six additional datasets.
Conclusions We detect global down-regulation of multiple proteasome subunits in schizophrenia which might lead to proteasome dysfunction, that can be the cause of the recently detected aggregation of ubiquitinated proteins. The concordance between 8 independent cohorts (267 schizophrenia, 266 control samples) remarkably strengthens the validity and robustness of our results.
Footnotes
The manuscript length was shortened, without any major changes.
Abbreviations
- SMRI
- Stanley Medical Research Institute;
- MSSM
- Mount Sinai School of Medicine;
- STG
- superior temporal gyrus;
- UPS
- Ubiquitin mediated proteasome system;
- PMI
- Post-mortem interval