CPEB1, a novel risk gene in recent-onset schizophrenia, contributes to mitochondrial complex I defect caused by a defective provirus ERVWE1

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.

ERVWE1 Reduces Hippocampal Neuron Density and Impairs Dendritic Spine Morphology through Inhibiting Wnt/JNK Non-Canonical Pathway via miR-141-3p in Schizophrenia

“…Consistent with our previous study [ 12 , 13 , 15 , 16 ], we also observed an increased levels of ERVWE1 mRNA and protein in schizophrenia patients ( Figure 1 H–I, Table S9 ). Further analysis revealed that miR-141-3p was positively correlated with ERVWE1 mRNA level ( p < 0.001, Figure 1 J).…”

“…But in some condition, certain ERVs are activated by external (ultraviolet (UV) [ 57 ], smoking [ 57 ], infections [ 58 ], and chemical drugs [ 59 ]), internal (morphogens, hormones, cytokines, and gene mutation), and epigenetic factors (DNA methylation and histone modification), which will ultimately cause diseases, MS [ 60 ], cancer [ 10 ], and schizophrenia [ 7 , 12 , 13 , 15 , 16 ]. HERVs contribute to development of disorders in various ways, such as assembling viral particles [ 2 ], acting as a promoter to regulate the expression of nearby cellular genes [ 8 ], or expressing viral proteins to regulate host cell signaling networks [ 12 , 13 , 15 , 16 , 61 , 62 , 63 , 64 , 65 ]. Our studies suggest an abnormal expression of ERVWE1 in schizophrenia [ 12 , 13 , 15 , 16 ].…”

“…HERVs contribute to development of disorders in various ways, such as assembling viral particles [ 2 ], acting as a promoter to regulate the expression of nearby cellular genes [ 8 ], or expressing viral proteins to regulate host cell signaling networks [ 12 , 13 , 15 , 16 , 61 , 62 , 63 , 64 , 65 ]. Our studies suggest an abnormal expression of ERVWE1 in schizophrenia [ 12 , 13 , 15 , 16 ]. Further studies indicate that ERVWE1 can directly activate Na + [ 16 ], Ca 2+ [ 14 , 61 ] or K + [ 14 , 62 ] ion channels, which are widely expressed in the central nervous system and implicate in the pathophysiology of schizophrenia [ 14 , 16 , 61 , 62 ].…”

“…Additionally, our research authenticates that ERVWE1 regulates the expression of brain derived neurotrophic factor (BDNF), one of schizophrenia risk gene, through glycogen synthase kinase 3β (GSK3β) phosphorylation at Ser9 [ 66 ]. Interestingly, we also discover that ERVWE1 contributes to mitochondrial dysfunction in neuron [ 15 ] and triggers abnormal dopaminergic neuron process through dopamine receptor D2 (DRD2) [ 16 ]. Together, ERVWE1 may contribute to the etiology of schizophrenia through a series of biological processes.…”

“…It is expressed in the placental syncytiotrophoblast and participates in syncytium formation during placenta morphogenesis [ 3 ]. Rapidly emerging evidence indicates that increased ERVWE1 activity has been suggested in several disease, including MS [ 6 ], urothelial cell carcinoma of the bladder (UCC) [ 9 ], hepatocellular carcinoma (HCC) [ 10 ], type 1 diabetes [ 11 ], and schizophrenia [ 12 , 13 , 14 , 15 , 16 ].…”