Comprehensive Gene Expression Analysis Detects Global Reduction of Proteasome Subunits in Schizophrenia.
gene expression
integrated analysis
postmortem brain samples
ubiquitin proteasome system
Journal
Schizophrenia bulletin
ISSN: 1745-1701
Titre abrégé: Schizophr Bull
Pays: United States
ID NLM: 0236760
Informations de publication
Date de publication:
29 04 2021
29 04 2021
Historique:
pubmed:
4
11
2020
medline:
23
11
2021
entrez:
3
11
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33141894
pii: 5953603
doi: 10.1093/schbul/sbaa160
pmc: PMC8084431
doi:
Substances chimiques
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
785-795Commentaires et corrections
Type : ErratumIn
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.
Références
Int Rev Neurobiol. 2005;63:41-82
pubmed: 15797465
Transl Psychiatry. 2019 May 9;9(1):147
pubmed: 31073119
Genome Med. 2017 Jul 28;9(1):72
pubmed: 28754123
Front Genet. 2018 Sep 28;9:434
pubmed: 30323833
Neuropsychopharmacology. 2013 Sep;38(10):1910-20
pubmed: 23571678
Nat Neurosci. 2016 Nov;19(11):1442-1453
pubmed: 27668389
Brain Res Bull. 2001 Jul 15;55(5):641-50
pubmed: 11576761
Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):494-502
pubmed: 19582768
Bioinformatics. 2005 May 15;21(10):2301-8
pubmed: 15722375
Am J Psychiatry. 2019 Sep 1;176(9):730-743
pubmed: 31055969
J Neurosci Res. 2011 Aug;89(8):1218-27
pubmed: 21538462
Biol Psychiatry. 2005 Jul 15;58(2):85-96
pubmed: 16038679
Mol Psychiatry. 2015 Nov;20(11):1397-405
pubmed: 25560755
Nucleic Acids Res. 2015 Jan;43(Database issue):D447-52
pubmed: 25352553
Am J Physiol Lung Cell Mol Physiol. 2016 Aug 1;311(2):L328-36
pubmed: 27343191
Bioinformatics. 2004 Nov 1;20(16):2778-86
pubmed: 15166021
Aust N Z J Psychiatry. 2012 Jul;46(7):598-610
pubmed: 22441207
Neuroscience. 2000;98(1):149-56
pubmed: 10858621
Schizophr Bull. 2011 May;37(3):504-13
pubmed: 21505117
J Chem Neuroanat. 2000 Oct;20(1):83-92
pubmed: 11074346
Immunol Today. 2000 Jul;21(7):317-9
pubmed: 10950502
Neuropsychopharmacology. 2016 Feb;41(3):896-905
pubmed: 26202105
J Hum Genet. 2009 Nov;54(11):665-75
pubmed: 19834500
Mol Psychiatry. 2009 Dec;14(12):1083-94
pubmed: 19255580
J Neurooncol. 2015 Oct;125(1):191-5
pubmed: 26285768
OMICS. 2016 Mar;20(3):139-51
pubmed: 26983021
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4746-51
pubmed: 11296301
J Neurooncol. 2016 Aug;129(1):139-46
pubmed: 27300524
Sci Rep. 2020 Jul 28;10(1):12655
pubmed: 32724114
Neurobiol Learn Mem. 2017 Feb;138:98-110
pubmed: 27614141
Mol Psychiatry. 2020 Apr;25(4):776-790
pubmed: 30683941
Br J Psychiatry Suppl. 2001 Apr;40:s18-24
pubmed: 11315219
Free Radic Biol Med. 2011 Jul 1;51(1):5-16
pubmed: 21530648
Schizophr Res. 2005 Sep 15;77(2-3):241-52
pubmed: 15923110
Sci Transl Med. 2018 Dec 19;10(472):
pubmed: 30545964
Sci Rep. 2019 Feb 19;9(1):2307
pubmed: 30783160
J Am Acad Child Adolesc Psychiatry. 2013 Apr;52(4):414-430.e14
pubmed: 23582872
Nucleic Acids Res. 2017 Jan 4;45(D1):D362-D368
pubmed: 27924014
J Neurosci. 2002 Apr 1;22(7):2718-29
pubmed: 11923437
Schizophr Bull. 2015 May;41(3):637-43
pubmed: 25528758
Nat Neurosci. 2003 Mar;6(3):231-42
pubmed: 12577062
Schizophr Res. 2000 Aug 3;44(2):151-5
pubmed: 10913747
Am J Med Genet B Neuropsychiatr Genet. 2010 Oct 5;153B(7):1336-41
pubmed: 20552680