4.6 Article

HERV-W Envelope Triggers Abnormal Dopaminergic Neuron Process through DRD2/PP2A/AKT1/GSK3 for Schizophrenia Risk

期刊

VIRUSES-BASEL
卷 14, 期 1, 页码 -

出版社

MDPI
DOI: 10.3390/v14010145

关键词

human endogenous retrovirus; HERV-W ENV; schizophrenia; dopamine receptor D2; dopaminergic systems; sodium influx

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资金

  1. National Natural Science Foundation of China [81971943, 81772196, 31470264, 81271820, 30870789, 30300117]
  2. Stanley Foundation from the Stanley Medical Research Institute (SMRI), United States [06R-1366]
  3. Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University [TFJC 2018002]

向作者/读者索取更多资源

The study reveals a relationship between HERV-W ENV and the dopaminergic system in schizophrenia, showing that HERV-W ENV can increase dopamine concentration by regulating dopamine metabolism and induce the expression of dopamine receptor D2. Additionally, HERV-W ENV causes structural and functional abnormalities in dopamine neurons.
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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