Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatr. Nov 19, 2021; 11(11): 1075-1094
Published online Nov 19, 2021. doi: 10.5498/wjp.v11.i11.1075
CPEB1, a novel risk gene in recent-onset schizophrenia, contributes to mitochondrial complex I defect caused by a defective provirus ERVWE1
Ya-Ru Xia, Xiao-Cui Wei, Wen-Shi Li, Qiu-Jin Yan, Xiu-Lin Wu, Wei Yao, Xu-Hang Li, Fan Zhu
Ya-Ru Xia, Xiao-Cui Wei, Wen-Shi Li, Qiu-Jin Yan, Xiu-Lin Wu, Wei Yao, Xu-Hang Li, Fan Zhu, State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy & Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
Author contributions: Xia YR designed and performed the experiments and wrote the manuscript; Yan QJ and Wu XL contributed to data collection; Yao W and Li XH performed some of the cytological experiments; Li WS and Wei XC conducted the data analyses; Zhu F served on the scientific advisory board for the School of Medicine, Wuhan University, conceived the study, was in charge of the overall direction and planning, drafted the manuscript, and the paid bills for this procedure.
Supported by the National Natural Science Foundation of China, No. 81971943, No. 81772196, No. 31470264, No. 81271820, No. 30870789, and No. 30300117; the Stanley Foundation of United States, No. 06R-1366 (for Zhu F); and the Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University, No. TFJC 2018002.
Institutional review board statement: The protocol of this study was approved by the Institutional Review Board of Wuhan University, School of Basic Medical Sciences, and the study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Informed consent was obtained for experimentation with human subjects and their privacy rights were always observed.
Conflict-of-interest statement: No potential conflicts of interest.
Data sharing statement: The data used and analyzed during the current study are available from the corresponding author upon request.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Fan Zhu, PhD, Director, Doctor, Professor, State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy & Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, No. 185 Donghu Road, Wuhan 430071, Hubei Province, China. fanzhu@whu.edu.cn
Received: April 25, 2021
Peer-review started: April 25, 2021
First decision: July 14, 2021
Revised: July 26, 2021
Accepted: August 25, 2021
Article in press: August 25, 2021
Published online: November 19, 2021
ARTICLE HIGHLIGHTS
Research background

Schizophrenia is a devastating psychiatric disorder that impairs mental and social functioning. There are several hypotheses regarding the pathogenesis of schizophrenia, including mitochondrial dysfunction. Both genetic and environmental factors contribute to the development of schizophrenia. Our previous studies showed that ERVWE1 acts as a bridge between genetic and environmental factors and plays an important role in the occurrence of schizophrenia.

Research motivation

Schizophrenia is a chronic disorder requiring long-term treatment and having a significant impact on patients and their families. Biomarkers and pathogenic mechanisms have become the most important undertaking for schizophrenia. In this manuscript, we focused on the relationship between mitochondrial energy metabolic deficits and ERVWE1 in schizophrenia.

Research objectives

This study aimed to identify novel potential blood-based biomarkers and risk factors for schizophrenia and to explore the underlying mechanisms ERVWE1-mediated mitochondrial metabolic deficits in schizophrenia.

Research methods

Quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay were used to detect differentially risk genes expression in blood samples. Statistical analyses of clinical data were performed by median analysis, Mann-Whitney U analysis, and Spearman’s rank correlation analysis. qPCR, western blotting, luciferase assay, and complex I enzyme activity microplate assay were performed to study the relationship between ERVWE1, CPEB1, NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), and NDUFV2 pseudogene (NDUFV2P1).

Research results

CPEB1 and NDUFV2 were deceased and negatively correlated with ERVWE1 in schizophrenia. Moreover, Increased NDUFV2P1 demonstrated a significant positive correlation with ERVWE1 and negative correlation with NDUFV2 in schizophrenia. Cytological experiments demonstrated that ERVWE1 suppressed CPEB1 by suppressing its promoter activity and downregulated NDUFV2 expression through increasing NDUFV2P1 transcript. Further studies showed that CPEB1 participated in regulating the NDUFV2P1/NDUFV2 axis mediated by ERVWE1 in SH-SY5Y cells. Finally, we found that ERVWE1 regulated complex I activity through the CPEB1/NDUFV2P1/NDUFV2 signaling pathway in SH-SY5Y cells.

Research conclusions

CPEB1 and NDUFV2 were identified as novel risk factors in schizophrenia. We also proposed a novel mechanism that ERVWE1 mediated mitochondria metabolic deficits through the CPEB1/NDUFV2P1/NDUFV2 signaling pathway in schizophrenia.

Research perspectives

Further study is needed to verify if CPEB1 and NDUFV2 can be used as blood-based biomarker of schizophrenia. As a risk factor, further efforts need to be focused on better understand the role of ERVWE1, CPEB1 and NDUFV2 in the pathogenesis of schizophrenia. Although our study suggests that ERVWE1 may be a potential therapeutic target for schizophrenia, whether ERVWE1 can really benefit clinical treatment requires further research in animal experiments and clinical trials to confirm these data.