CPEB1, a novel risk gene in recent-onset schizophrenia, contributes to mitochondrial complex I defect caused by a defective provirus ERVWE1.
CPEB1, a novel risk gene in recent-onset schizophrenia, contributes to mitochondrial complex I defect caused by a defective provirus ERVWE1.
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CPEB1 是新发精神分裂症的一种新风险基因，它会导致由有缺陷的原病毒 ERVWE1 引起的线粒体复合物 I 缺陷。
DOI：
10.5498/wjp.v11.i11.1075
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发表时间：
2021-11-19
影响因子：
3.1
通讯作者：
Zhu F
中科院分区：
文献类型：
--
作者：
Xia YR;Wei XC;Li WS;Yan QJ;Wu XL;Yao W;Li XH;Zhu F
精神分裂症折磨着世界上1%的人口。临床研究表明，精神分裂症患者可能通过抑制线粒体复合体I活性而存在线粒体能量代谢失衡。此外，最近的研究表明，ERVWE1也是精神分裂症的一个危险因素。然而，目前尚无关于精神分裂症患者复合体I缺陷与ERVWE1之间关系的文献。识别精神分裂症的危险因素和血液生物标志物可能为早期干预和预防计划提供新的指导。探讨由ERVWE1引起的精神分裂症线粒体复合体I缺乏的新潜在危险因素和潜在机制。采用定量聚合酶链反应（qPCR）和酶联免疫吸附法检测血液样本中差异表达的危险因素。临床统计学分析采用中位数分析和Mann-Whitney U分析。应用Spearman等级相关来检验血液样本中不同危险因素之间的相关性。采用qPCR、western blot和荧光素酶检测证实ERVWE1与胞质多聚腺苷化元件结合蛋白1 （CPEB1）、NADH脱氢酶泛素黄蛋白2 （NDUFV2）和NDUFV2假基因（NDUFV2P1）之间的关系。采用复合物I酶活性微孔板法评价ERVWE1诱导复合物I酶活性。本文中，我们报道了精神分裂症患者CPEB1和NDUFV2水平下降。进一步研究表明，精神分裂症患者ERVWE1与CPEB1和NDUFV2呈负相关。精神分裂症患者NDUFV2P1水平升高，与ERVWE1呈显著正相关，与NDUFV2呈负相关。体外实验发现，ERVWE1通过提高NDUFV2P1水平抑制NDUFV2的表达和启动子活性。荧光素酶实验表明，ERVWE1可以增强NDUFV2P1启动子的活性。此外，ERVWE1通过抑制启动子活性下调CPEB1的表达，启动子3 '端的400碱基对序列是所需的最小序列。进一步研究表明，CPEB1参与了ERVWE1介导的NDUFV2P1/NDUFV2轴的调控。最后，我们发现ERVWE1通过CPEB1/NDUFV2P1/NDUFV2信号通路抑制SH-SY5Y细胞中复合物I的活性。综上所述，CPEB1和NDUFV2可能是精神分裂症新的潜在血液生物标志物和致病因子。我们的研究结果还揭示了ERVWE1在精神分裂症病因学中的新机制。
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. To address novel potential risk factors and the underlying mechanisms of mitochondrial complex I deficiency caused by ERVWE1 in schizophrenia. 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. 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. 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.
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