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
Abstract
BACKGROUND

Schizophrenia afflicts 1% of the world population. Clinical studies suggest that schizophrenia patients may have an imbalance of mitochondrial energy metabolism via inhibition of mitochondrial complex I activity. Moreover, recent studies have shown that ERVWE1 is also a risk factor for schizophrenia. Nevertheless, there is no available literature concerning the relationship between complex I deficits and ERVWE1 in schizophrenia. Identifying risk factors and blood-based biomarkers for schizophrenia may provide new guidelines for early interventions and prevention programs.

AIM

To address novel potential risk factors and the underlying mechanisms of mitochondrial complex I deficiency caused by ERVWE1 in schizophrenia.

METHODS

Quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay were used to detect differentially expressed risk factors in blood samples. Clinical statistical analyses were performed by median analyses and Mann-Whitney U analyses. Spearman’s rank correlation was applied to examine the correlation between different risk factors in blood samples. qPCR, western blot analysis, and luciferase assay were performed to confirm the relationship among ERVWE1, cytoplasmic polyadenylation element-binding protein 1 (CPEB1), NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), and NDUFV2 pseudogene (NDUFV2P1). The complex I enzyme activity microplate assay was carried out to evaluate the complex I activity induced by ERVWE1.

RESULTS

Herein, we reported decreasing levels of CPEB1 and NDUFV2 in schizophrenia patients. Further studies showed that ERVWE1 was negatively correlated with CPEB1 and NDUFV2 in schizophrenia. Moreover, NDUFV2P1 was increased and demonstrated a significant positive correlation with ERVWE1 and a negative correlation with NDUFV2 in schizophrenia. In vitro experiments disclosed that ERVWE1 suppressed NDUFV2 expression and promoter activity by increasing NDUFV2P1 level. The luciferase assay revealed that ERVWE1 could enhance the promoter activity of NDUFV2P1. Additionally, ERVWE1 downregulated the expression of CPEB1 by suppressing the promoter activity, and the 400 base pair sequence at the 3′ terminus of the promoter was the minimum sequence required. Advanced studies showed that CPEB1 participated in regulating the NDUFV2P1/NDUFV2 axis mediated by ERVWE1. Finally, we found that ERVWE1 inhibited complex I activity in SH-SY5Y cells via the CPEB1/NDUFV2P1/NDUFV2 signaling pathway.

CONCLUSION

In conclusion, CPEB1 and NDUFV2 might be novel potential blood-based biomarkers and pathogenic factors in schizophrenia. Our findings also reveal a novel mechanism of ERVWE1 in the etiology of schizophrenia.

Keywords: ERVWE1, CPEB1, NADH dehydrogenase ubiquinone flavoprotein 2, complex I, Pseudogene

Core Tip: Schizophrenia is a devastating psychiatric disorder. Clinical studies suggest complex I deficits and abnormal expression of ERVWE1 in schizophrenia. We found that CPEB1 might be a novel blood-based biomarker for schizophrenia. Analyses indicated that ERVWE1 was negatively correlated with CPEB1 and NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2) in schizophrenia patients. CPEB1 functioned as a mediator of the NDUFV2 pseudogene (NDUFV2P1)/NDUFV2 pathway induced by ERVWE1. Moreover, ERVWE1 inhibited complex I activity via the CPEB1/NDUFV2P1/NDUFV2 pathway. Thus, CPEB1 and NDUFV2 may be independent risk factors for schizophrenia. Our findings also reveal the role of ERVWE1 in modulating mitochondrial energy metabolism in schizophrenia.