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

Abstract

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 recentonset 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 schizophreniaassociated 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.

Pathophysiological Role of HERV-W in Schizophrenia

“…47 This finding suggests a role of HERV-W in schizophrenia-associated BDNF and DRD3 abnormalities. Some HERVs use neuroactive molecules as receptors.…”

“…Huang et al 47 sought to detect genes with mRNA sequences homologous to the HERV-W env gene in the plasma of 118 patients with recent-onset schizophrenia and 106 normal control participants. The authors found the genes in 42 of 118 patients (35.6%) but in none of the control participants.…”

Les rétrovirus endogènes humains, une implication dans la schizophrénie et le trouble bipolaire

“…Cette augmentation a également été retrouvée au niveau des cellules mononucléées du sang (PBMC) isolées des patients entrant dans la schizophrénie avec une expression accrue de HERV-W gag, de 2 fois par rapport aux témoins [27]. Une corrélation inverse entre niveau d'expression du HERV-W et durée de la maladie semble aussi exister [27] et HERV-W env est surexprimée chez les sujets SCZ et TB [28], associée à une activité transcriptase inverse augmentée d'environ 36 % [29]. La présence dans le sang, d'antigènes codés par HERV-W gag et HERV-W env est observée chez environ la moitié des patients SCZ (des mêmes patients étant positifs pour les deux antigènes, la révélation de HERV-W env étant réalisée par deux anticorps monoclonaux différents) [30].…”

Viral metagenomics in drug-naïve, first-onset schizophrenia patients with prominent negative symptoms

“…Gene-environment interactions may be involved in the development of vulnerability and prominent negative symptoms may be regarded as a characteristic of severe type of the disorder, possibly associated with neurodegeneration (Tsuang, 2000;Huang et al, 2011). Connections between the onset of schizophrenia and viral infections are reported, indicating that viral infections may play a role in the etiopathogenesis of schizophrenia (Arias et al, 2012).…”

“…Although the majority of them have become mutated and truncated, a few have retained the capacity to encode viral proteins, still contain intact promoters or are able to form virus-like particles (Boller et al, 2008). Moreover, novel HERV loci can be generated by recombination/(retro) transposition during gestation, creating modifications in the embryonic DNA (Subramanian et al, 2011), and some HERVs are mobile genetic elements which may be regulated/activated by environmental factors, such as microbial agents, and can induce genetic rearrangements (Huang et al, 2011;Feschotte and Gilbert, 2012). An association between endogenous retrovirus activation and schizophrenia has been supported by several studies (Lillehoj et al, 2000;Yolken et al, 2000;Karlsson et al, 2001Karlsson et al, , 2004Perron et al, 2008;Leboyer et al, 2013).…”