精神分裂症中HERV-W家族包膜(ERVWE1)基因过表达致突触异常的分子机制研究

Human endogenous retroviruses (HERVs) made up as much as 8% in the human genome. HERV-W(also called Multiple Sclerosis associated RetroVirus, MSRV) was one of the families of HERVs. Recent studies showed that there was a close relationship between the HERV-W envelope (also called ERVWE1) gene and many diseases, such as schizophrenia, MS (Multiple Sclerosis), cancer, and so on. Clinical study also showed there were degeneration of synaptic function and disorder of neurotransmitter in schizophrenia patients. Our data showed that the overexpression of ERVWE1 gene in neurocytes led to the expression of many factors which are associated with schizophernia, such as BDNF(brain derived neurotrophic factor), S100B, CXCL10(C-X-C motif chemokine 10), SK3(small conductance calcium-activated channel, subfamily N, member 3), etc. More interesting, we found that the overexpression of ERVWE1 gene in neurocytes downregulated the expression of SYN I (synapsin I) and SYP (synaptophysin), two Synaptic vesicle membrane proteins. While the expression of PSD95 (postsynaptic density 95) were upregulated by ERVWE1. ERVWE1 also upregulated the expression of some receptors of the neurotransmitters, such as D3DR(D3 dopamine receptor), GluN1, GluN3A and GluN3B . From above on, based on the 4 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 “Study on the molecular neurobiological mechanisms of Synaptic abnormality induced by the overexpression of HERV-W env (ERVWE1) in schizophernia", using molecular biology, bioinformatics, electrophysiology and other biotechnologies. Therefore we will carry out this study from six areas:1.The overexpression of ERVWE1 gene leads to disorganization of presynaptic membrane in neurocytes; 2.The overexpression of ERVWE1 gene leads to postsynaptic membrane abnormalities and changes of synaptic numbers in neurocytes;3.The overexpression of ERVWE1 gene leads to abnormalities of the synaptic vesicle in neurocytes;4.The overexpression of ERVWE1 gene leads to abnormalities of the synaptic transmission in neurocytes; 5..The overexpression of ERVWE1 gene leads to abnormalities in neurotransmitters and their receptors in neurocytes;6.Study of abnormalities of synaptic function caused by the overexpression of ERVWE1 gene using electrophysiological study. .For this study, we will show the effect of the ERVWE1 gene on the synapses, synaptic transmission, neurotransmitters and their receptors, and also function of synapses. We will also reveal a new pathway of how ERVWE1 gene causes neuropsychiatric disorders such as schizophernia, MS etc. And all these would provide new ideas about mechanism of how ERVWE1 gene causes diseases and provide new ideas for treatment of some neuropsychiatric disorders, such as schizophernia, MS etc.

人内源性逆转录病毒W家族包膜(ERVWE1)基因过表达与精神分裂症密切相关，精神分裂症患者中存在突触功能的退化及神经递质传递紊乱。我们前期研究发现ERVWE1在神经细胞中过表达可导致突触囊泡膜蛋白SYN I（囊泡锚定蛋白I）与SYP（囊泡整合蛋白）的表达明显下降；突触后膜蛋白PSD95（突触后致密物95）表达却上升；多巴胺受体D3DR，谷氨酸的离子型受体NMDA受体中3个亚单位GluN1、GluN3A、GluN3B等神经递质受体的表达水平也显著升高。因此我们拟从ERVWE1基因过表达致突触结构与功能异常、ERVWE1基因过表达致突触传递（囊泡动员、着位、与前膜融合）异常、ERVWE1基因过表达致神经递质及受体和转运体异常等几个方面，来探讨精神分裂症中ERVWE1基因过表达致突触异常的分子机制。本项目可为证实ERVWE1的潜在致病作用提供直接证据，也可帮助临床医生更好地预防和治疗精神分裂症。

人内源性逆转录病毒W家族包膜(ERVWE1)基因过表达与精神分裂症密切相关，精神分裂症患者中存在突触功能的退化及神经递质传递紊乱。在本项目中，我们从ERVWE1基因过表达致突触结构与功能异常、ERVWE1基因过表达致突触传递（囊泡动员、着位、与前膜融合）异常、ERVWE1基因过表达致神经递质及受体和转运体异常等几个方面开展了相关研究，结果发现：精神分裂症患者中，多巴胺浓度与多巴胺受体DRD2明显高于健康对照组，且与ERVWE1的表达呈正相关性；进一步研究发现ERVWE1可通过调控多巴胺合成与转运导致多巴胺浓度升高；ERVWE1可升高DRD2的表达，且2者存在共定位及相互作用；ERVWE1可导致多巴胺能突触前膜蛋白、后膜蛋白的升高；深入研究发现ERVWE1可诱导PP2A/AKT/GSK3信号通路的活化，且DRD2介导了ERVWE1对突触前后膜蛋白的调控及PP2A/AKT/GSK3信号通路的活化；ERVWE1还可增强多巴胺能神经元的钠离子内流。我们还发现精神分裂症患者中，5-羟色胺受体4（HTR4）表达明显低于正常人，且与ERVWE1的表达呈负相关性；进一步研究发现ERVWE1可导致小电导钙激活的钾离子通道蛋白（SK2）的升高，进而激活SK2通路。本项目初步探讨了精神分裂症中ERVWE1基因过表达致突触异常的分子机制。本项目的完成直接证实了ERVWE1能引起神经元突触异常，进而导致神经元功能异常，为证实ERVWE1的潜在致病作用提供直接证据，也为临床治疗精神分裂症提供了新的靶标。