HERV-W Envelope Triggers Abnormal Dopaminergic Neuron Process through DRD2/PP2A/AKT1/GSK3 for Schizophrenia Risk.
HERV-W Envelope Triggers Abnormal Dopaminergic Neuron Process through DRD2/PP2A/AKT1/GSK3 for Schizophrenia Risk.
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DOI：
10.3390/v14010145
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发表时间：
2022-01-14
期刊：
影响因子：
--
通讯作者：
Zhu F
中科院分区：
文献类型：
--
作者：
Yan Q;Wu X;Zhou P;Zhou Y;Li X;Liu Z;Tan H;Yao W;Xia Y;Zhu F
越来越多的研究开始认为人类内源性逆转录病毒(HERV)是潜在的致病现象。我们先前的研究表明，HERV-W包膜蛋白(Herv-W ENV)是一种HERV-W家族包膜蛋白，在精神分裂症患者中表达升高，并与精神分裂症的病理生理有关。多巴胺(DA)假说是精神分裂症相关研究和临床实践的基石。在这里，我们发现精神分裂症患者的多巴胺浓度和多巴胺受体D2(DRD2)的表达显著高于健康人。有趣的是，HERV-W ENV与DA浓度呈正相关。深度分析显示，精神分裂症患者的HERV-W ENV与DRD2有显著的一致性。体外研究表明，HERV-W ENV可通过调节DA代谢增加DA浓度，诱导DRD2的表达。共免疫印迹分析和激光共聚焦扫描显微镜显示DRD2和HERV-W ENV之间存在细胞共定位和直接相互作用。此外，HERV-W ENV还可引起DA神经元结构和功能的异常。进一步研究表明，HERV-W ENV可通过DRD2途径启动PP2A/AKT1/GSK3通路。全细胞膜片钳分析表明，Herv-W ENV通过DRD2促进钠内流。总之，我们揭示了Herv-W ENV与DA神经元中的多巴胺能系统之间的关系。考虑到针对MSRV特异性表位的选择性单抗GNbAC1已被用于治疗1型糖尿病和多发性硬化症(MS)的临床试验，了解Herv-W ENV在多巴胺能系统中的准确功能可能为精神分裂症的治疗提供新的见解。
An increasing number of studies have begun considering human endogenous retroviruses (HERVs) as potential pathogenic phenomena. Our previous research suggests that HERV-W Envelope (HERV-W ENV), a HERV-W family envelope protein, is elevated in schizophrenia patients and contributes to the pathophysiology of schizophrenia. The dopamine (DA) hypothesis is the cornerstone in research and clinical practice related to schizophrenia. Here, we found that the concentration of DA and the expression of DA receptor D2 (DRD2) were significantly higher in schizophrenia patients than in healthy individuals. Intriguingly, there was a positive correlation between HERV-W ENV and DA concentration. Depth analyses showed that there was a marked consistency between HERV-W ENV and DRD2 in schizophrenia. Studies in vitro indicated that HERV-W ENV could increase the DA concentration by regulating DA metabolism and induce the expression of DRD2. Co-IP assays and laser confocal scanning microscopy indicated cellular colocalization and a direct interaction between DRD2 and HERV-W ENV. Additionally, HERV-W ENV caused structural and functional abnormalities of DA neurons. Further studies showed that HERV-W ENV could trigger the PP2A/AKT1/GSK3 pathway via DRD2. A whole-cell patch-clamp analysis suggested that HERV-W ENV enhanced sodium influx through DRD2. In conclusion, we uncovered a relationship between HERV-W ENV and the dopaminergic system in the DA neurons. Considering that GNbAC1, a selective monoclonal antibody to the MSRV-specific epitope, has been promised as a therapy for treating type 1 diabetes and multiple sclerosis (MS) in clinical trials, understanding the precise function of HERV-W ENV in the dopaminergic system may provide new insights into the treatment of schizophrenia.
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