Implication of the env Gene of the Human Endogenous Retrovirus W Family in the Expression of BDNF and DRD3 and Development of Recent-Onset Schizophrenia
Implication of the env Gene of the Human Endogenous Retrovirus W Family in the Expression of BDNF and DRD3 and Development of Recent-Onset Schizophrenia
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DOI：
10.1093/schbul/sbp166
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发表时间：
2011-09-01
影响因子：
6.6
通讯作者：
Zhu, Fan
中科院分区：
文献类型：
--
作者：
Huang, WenJie;Li, Shan;Zhu, Fan
目的：逆转录病毒被认为是参与精神分裂症发病的因子之一。在本研究中，我们研究了人类内源性逆转录病毒W家族（HERV-W）env基因在新发精神分裂症发病机制中的作用，采用分子和流行病学方法。方法：采用巢式RT-PCR检测血浆中HERV-w env基因的mRNA。采用实时定量聚合酶链反应（PCR）检测人血清中病毒逆转录酶活性。利用人U251胶质瘤细胞研究HERV-W env基因在新发精神分裂症发病机制中的潜在作用。结果如下：我们从118例精神分裂症患者中的42例血浆中检测到与HERV-W env基因同源的基因，而在106例正常人中没有检测到（P <0.01，t检验）。实时荧光定量PCR显示，患者血清中逆转录酶活性（35.59%）与对照组（2.83%）相比显著增加（P <0.05，t检验）。HERV-w env在人U251胶质瘤细胞中的过表达上调了脑源性神经营养因子（BDNF）（一种重要的精神分裂症相关基因）、神经营养酪氨酸激酶受体2（NTRK 2，也称为TrkB）和多巴胺受体D3，并增加了环磷酸腺苷反应元件结合（CREB）蛋白的磷酸化。BDNF启动子报告基因分析表明HERV-W env在人U251胶质瘤细胞中触发BDNF的产生。通过基因敲除，我们发现CREB是由env调控的BDNF表达所必需的。结论：我们的数据显示，HERV的转录激活与精神分裂症的发展在一些患者，并表明HERV-W env调节精神分裂症相关基因的表达。该报告首次阐明了HERV-W env触发的BDNF上调的信号通路。我们的研究为HERV-W参与中枢神经系统提供了新的证据，这将有利于毁灭性精神分裂症及其相关疾病的诊断和治疗。
Objective: Retrovirus has been suggested as one of agents involved in the development of schizophrenia. In the present study, we examined the role of the human endogenous retrovirus W family (HERV-W) env gene in the etiopathogenesis of recent-onset schizophrenia, using molecular and epidemiological approaches. Methods: Nested RT-PCR was used to detect the messenger RNA (mRNA) of the HERV-w env gene in plasmas. Quantitative real-time polymerase chain reaction (PCR) was employed to detect the viral reverse transcriptase activity in human sera. Human U251 glioma cells were used to study the potential role of the HERV-W env gene in the etiopathogenesis of recent-onset schizophrenia. Results: We identified genes with mRNA sequences homologous to HERV-W env gene from plasmas of 42 out of 118 individuals with recent-onset schizophrenia but not from any of 106 normal persons (P < .01, t test). Quantitative real-time PCR showed a significantly increase in the reverse transcriptase activity in the sera of patients (by 35.59%) compared with controls (by 2.83%) (P < .05, t test). Overexpression of HERV-w env in human U251 glioma cells upregulated brain-derived neurotrophic factor (BDNF), an important schizophrenia-associated gene, neurotrophic tyrosine kinase receptor type 2 (NTRK2, also called TrkB), and dopamine receptor D3 and increased the phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein. BDNF promoter reporter gene assays showed that the HERV-W env triggers BDNF production in human U251 glioma cells. Using gene knockdown, we found that CREB is required for the expression of BDNF that is regulated by env. Conclusion: Our data revealed that the transcriptional activation of HERV is associated with the development of schizophrenia in some patients and indicated that HERV-W env regulates the expression of schizophrenia-associated genes. This report is the first to elucidate the signaling pathway responsible for the upregulation of HERV-W env-triggered BDNF. Our study provides new evidence for the involvement of HERV-W in the central nervous system, which will benefit the diagnosis and treatment of the devastating schizophrenia and related disorders.