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

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.

Genetic variation and phylogenetic relationship of Hypoderaeum conoideum(Bloch, 1782) Dietz, 1909(Trematoda: Echinostomatidae) inferred from nuclear and mitochondrial DNA sequences

Objective:To explore genetic variations of Hypoderaeum conoideum collected from domestic ducks from 12 different localities in Thailand and Lao PDR,as well as their phylogenetic relationship with American and European isolates.Methods:The nucleotide sequences of their nuclear ribosomal DNA(ITS),mitochondrial cytochrome c oxidase subunit 1(CO1),and NADH dehydrogenase subunit 1(ND1)were used to analyze genetic diversity indices.Results:We found relatively high levels of nucleotide polymorphism in ND1(4.02%),whereas moderate and low levels were observed in CO1(2.11%)and ITS(0.96%),respectively.Based on these polymorphisms,the 20 ND1,12 CO1,and 18 ITS haplotypes were classified,and several common haplotypes were observed in all samples.At least three major lineages,namely American,European and Asian lineages,have been classified by phylogenetic analyses based on ND1 sequences.Conclusions:Our report demonstrates that the ND1 gene is the most suitable genetic marker to explore genetic variation and phylogenetic relationship of Hypoderaeum conoideum.However,a combination of all loci for ND1,CO1 and ITS would be of great value toward further genetic investigation of this endemic worldwide parasite.Thus,comprehensive molecular genetic analyses of Hypoderaeum conoideum from its worldwide distribution is needed to further understanding of the evolutionary and systematic relationships of this parasite.