Comprehensive Gene Expression Analysis Detects Global Reduction of Proteasome Subunits in Schizophrenia

Libi Hertzberg*, Nicola Maggio, Inna Muler, Assif Yitzhaky, Michael Majer, Vahram Haroutunian, Or Zuk, Pavel Katsel, Eytan Domany, Mark Weiser

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Background: The main challenge in the study of schizophrenia is its high heterogeneity. While it is generally accepted that there exist several biological mechanisms that may define distinct schizophrenia subtypes, they have not been identified yet. We performed comprehensive gene expression analysis to search for molecular signals that differentiate schizophrenia patients from healthy controls and examined whether an identified signal was concentrated in a subgroup of the patients. Methods: Transcriptome sequencing of 14 superior temporal gyrus (STG) samples of subjects with schizophrenia and 15 matched controls from the Stanley Medical Research Institute (SMRI) was performed. Differential expression and pathway enrichment analysis results were compared to an independent cohort. Replicability was tested on 6 additional independent datasets. Results: The 2 STG cohorts showed high replicability. Pathway enrichment analysis of the down-regulated genes pointed to proteasome-related pathways. Meta-analysis of differential expression identified down-regulation of 12 of 39 proteasome subunit genes in schizophrenia. The signal of proteasome subunits down-regulation was replicated in 6 additional datasets (overall 8 cohorts with 267 schizophrenia and 266 control samples, from 5 brain regions). The signal was concentrated in a subgroup of patients with schizophrenia. Conclusions: We detected global down-regulation of proteasome subunits in a subgroup of patients with schizophrenia. We hypothesize that the down-regulation of proteasome subunits leads to proteasome dysfunction that causes accumulation of ubiquitinated proteins, which has been recently detected in a subgroup of schizophrenia patients. Thus, down-regulation of proteasome subunits might define a biological subtype of schizophrenia.

Original languageAmerican English
Pages (from-to)785-795
Number of pages11
JournalSchizophrenia Bulletin
Issue number3
StatePublished - 1 May 2021

Bibliographical note

Publisher Copyright:
© 2020 The Author(s). Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email:


  • gene expression
  • integrated analysis
  • postmortem brain samples
  • ubiquitin proteasome system


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