精神分裂症中HERV-W家族包膜基因（ERVWE1）过表达致神经细胞线粒体异常的研究

人内源性逆转录病毒W家族包膜基因(ERVWE1)过表达与精神分裂症密切相关，致病机制未明，而精神分裂症患者中存在线粒体结构与功能异常以及氧化应激损伤。我们研究发现ERVWE1在神经细胞中过表达可导致线粒体DNA编码的基因（MT-CYB、MT-ND3、MT-ATP6、MT-ATP8等）表达水平改变；MFN1、MFN2、MFF等线粒体动力学相关基因表达上升；参与氧化磷酸化lncRNA NEAT2的表达水平下降；调控线粒体凋亡途径的lncRNA MEG3的表达水平升高。因此我们拟从ERVWE1基因过表达致神经细胞线粒体结构损伤、生物合成异常、生物氧化呼吸链障碍、氧化应激损伤、凋亡途径异常和动力学失衡等几个方面，探讨精神分裂症中ERVWE1基因过表达致神经细胞线粒体结构与功能异常的机制，阐明ERVWE1基因过表达致神经细胞能量代谢异常的分子机制，揭示ERVWE1过表达在精神分裂症发生发展中的作用。

Recent studies show that there is a close relationship between overexpression of Human endogenous retrovirus W family envelop(HERV-W env, also called ERVWE1). The pathogenic mechanism is not clearly. Clinical studies show metabolic dysfunction and energy supply and demand mismatch have been implicated in schizophrenia. Our data showed that the overexpression of ERVWE1 gene in neurocytes upregulated the genes encoded by mitochondrial DNA(mtDNA), such as MT-CYB, MT-ND3, MT-ATP6, MT-ATP8, MT-TS1, MT-RNA2, etc. The expression levels of genes involved in mitochondrial dynamics, such as MFN1, MFN2 and MFF, also increased after overexpression of ERVWE1 gene in neurocytes. More interesting, we found that the expression of NEAT2, a lncRNA which could regulate the oxidative phosphorylation, decreased after transfected with ERVWE1 in neurocytes. Moreover, the expression level of lncRNA MEG3, which could regulate mitochondrial apoptosis pathway, increased in neurocytes transfected with ERVWE1. We hypothesize that overexpression of ERVWE1 might cause structural abnormalities of mitochondria, abnormal mitochondrial dynamics and deficits in mitochondrial bioenergetics. And then these would lead to schizophrenia. From above on, based on the 5 Foundations from National Natural Science Foundation of China and 1 foundation from Stanley Stanley Medical Foundation, of which all are taken charge by the applicant, we will carry out “overexpression of HERV-W envelope induces abnormal of mitochondria in nerve cells in schizophrenia” using molecular biology, bioinformatics, electrophysiology and other biotechnologies. Therefore, we try to explore the role of ERVWE1 gene in schizophrenia from the mitochondrial structural damage, abnormalities in the biosynthesis, mitochondrial respiratory chain disorders, oxidative stress, abnormalities in mitochondrial apoptotic pathway and imbalance of mitochondrial dynamics induced by overexpression of ERVWE1 gene in neurocytes. For this study, we will discover the mechanism of mitochondrial structure and dysfunction and reveal the molecular mechanism of abnormalities in energy metabolism caused by overexpression of ERVWE1 gene in schizophrenia. And we will also elucidate the role of ERVWE1 in the development of schizophrenia.