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

Qiujin Yan,Ping Zhou,Yan Zhou,Xiulin Wu,Fan Zhu,Huawei Tan,Wei Yao,Zhongchun Liu,Yaru Xia,Xuhang Li

doi:10.3390/v14010145

Abstract

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.

Highlights

Endogenous retroviruses (ERVs) are present in the genomes of all vertebrates, as well as in some invertebrates [1]
Further studies found that human endogenous retroviruses (HERVs)-W ENV activated the dopaminergic system by upregulating the DA receptor D2 (DRD2) and synaptic proteins
Bioinformatics Analysis Demonstrates That DRD1, DRD2, and GSK3 Are Implicated in Schizophrenia

Summary

Introduction

Endogenous retroviruses (ERVs) are present in the genomes of all vertebrates, as well as in some invertebrates [1]. Since being discovered in 1981 [2], human endogenous retroviruses (HERVs) constitute about 8% of the human genome [3]. Abnormal expression of HERV-W ENV, a HERV-W envelope protein, has been intensively investigated for its putative role in several diseases, such as bladder cancer [5], multiple sclerosis (MS) [6], hepatocellular carcinoma [7], type 1 diabetes [8], and bipolar disorder [9]. The HERV-W family draws the attention of most researchers who study HERVs because of its founder member, multiple sclerosis-associated retroviruses (MSRV), a complete virus with extracellular virions. Quite a few studies suggest that HERV-W ENV constitute a possible link between genetic components and environmental factors in schizophrenia [10,11,12,13,14,15]. Investigation into HERV-W ENV will further our understanding of the molecular basis of schizophrenia pathogenesis

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