| Abstract | Human endogenous retrovirus W family (HERV-W) envelope (env) is known to be associated with neurological and psychiatric disorders, such as multiple sclerosis and schizophrenia. Previous studies showed that overexpression of HERV-W env could induce brain-derived neurotrophic factor (BDNF) gene expression. In human and rat cells, BDNF-mediated signal transduction might be modulated by glycogen synthase kinase 3? (GSK3?). Both BDNF and GSK3? are schizophrenia-related genes. In this paper, we investigated whether GSK3? was involved in the HERV-W env-induced expression of BDNF. We found that HERV-W env increased phosphorylation of GSK3? at Ser9 (p-GSK3? (Ser9)) and the ratio of p-GSK3? (Ser9) to total GSK3? (p<0.05) in U251 cells. Overexpression of HERV-W env led to a 36% reduction in GSK3? activity compared to control (p<0.05). The levels of ?-catenin, cyclin D1 and TSC2 mRNAs were upregulated (p<0.05). These data suggested that overexpression of HERV-W env might activate the GSK3? signaling pathway in U251 cells. Further, knockdown of GSK3? reduced the expression of total GSK3?, p-GSK3? (Ser9), and the ratio of p-GSK3? (Ser9) to total GSK3? by 29%, 50%, and 31%, respectively (p<0.05). Levels of ?-catenin, cyclin D1 and TSC2 mRNAs were also reduced (p<0.05). Interestingly, GSK3? activity increased (p<0.05). Knockdown of GSK3? also decreased mRNA and protein expression of BDNF by 36% and 48% respectively (p<0.05). These results indicated that phosphorylation of GSK3? at Ser9 might be involved in HERV-W env-induced BDNF expression, and will hopefully improve our understanding of the role of HERV-W env in neurological and psychiatric diseases (schizophrenia, etc). |