Department of Medical Microbiology, School of Medicine, Wuhan University, 185 Donghu Road, Wuhan 430071, People's Republic of China.
Schizophr Bull. 2011 Sep;37(5):988-1000. doi: 10.1093/schbul/sbp166. Epub 2010 Jan 25.
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.
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.
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.
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.
逆转录病毒已被认为是导致精神分裂症的因素之一。本研究采用分子流行病学方法，探讨人类内源性逆转录病毒 W 家族（HERV-W）env 基因在首发精神分裂症发病机制中的作用。
采用巢式 RT-PCR 检测血浆中人内源性逆转录病毒 W 基因的信使 RNA（mRNA），采用实时定量聚合酶链反应（PCR）检测人血清中的病毒逆转录酶活性。用人 U251 神经胶质瘤细胞研究 HERV-W env 基因在首发精神分裂症发病机制中的潜在作用。
我们从 118 例首发精神分裂症患者中的 42 例血浆中鉴定出与 HERV-W env 基因 mRNA 序列同源的基因，但从 106 例正常人中未鉴定出（P<0.01，t 检验）。实时定量 PCR 显示患者血清中的逆转录酶活性明显升高（增加 35.59%），而对照组则明显降低（增加 2.83%）（P<0.05，t 检验）。在人 U251 神经胶质瘤细胞中过表达 HERV-W env 可上调脑源性神经营养因子（BDNF），BDNF 是一种与精神分裂症相关的重要基因，神经生长因子酪氨酸激酶受体 2（NTRK2，也称为 TrkB）和多巴胺受体 D3，增加环磷酸腺苷反应元件结合蛋白（CREB）的磷酸化。BDNF 启动子报告基因检测显示，HERV-W env 可触发人 U251 神经胶质瘤细胞产生 BDNF。通过基因敲低，我们发现 CREB 是 HERV-W env 调节的 BDNF 表达所必需的。
我们的数据表明，HERV 的转录激活与某些患者精神分裂症的发展有关，并表明 HERV-W env 调节与精神分裂症相关的基因表达。本研究首次阐明了 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，这将有助于精神分裂症及相关疾病的诊断和治疗。
