Neuropathogenic effects of Syncytin-1 in Multiple Sclerosis

Human endogenous retroviruses (HERVs) constitute 8% of the human genome and have been implicated in both health and disease. Increased HERV gene activity occurs in activated glia although the consequences of HERV expression in the nervous system remain uncertain. Relative quantification and quantitative PCR analysis of HERV envelopes (env) revealed selectively increased abundance of HERV-W-7q encoded glycoprotein, Syncytin-1 in brains but not in blood-derived leukocytes from patients with Multiple Sclerosis (MS) relative to non-MS patients. Syncytin-1 expression in astrocytes induced the release of redox reactants, which were cytotoxic to oligodendrocytes. Increase in Syncytin-1 expression in astrocytes in the brain white matter of MS patients was accompanied by induction of the ER stress genes, OASIS, BiP, PERK, and GADD153. Expression of OASIS in astrocytes induced iNOS and thus, nitric oxide. ASCT-1, a neutral amino acid transporter and Syncytin-1 receptor, was suppressed in brain white matter astrocytes of MS patients and also in astrocytes expressing Syncytin-1 or OASIS. Nitric oxide enhanced the expression of the repressor transcription factor, Egr1, which concurrently suppressed ASCT1. Syncytin-1 mediated neuroinflammation and death of oligodendrocytes with ensuing neurobehavioral deficits were prevented by the antioxidant ferulic acid in a mouse model of MS. TNF-alpha implantation into a novel Syncytin-1 transgenic mice induced ER stress, loss of ASCT1 complemented by glial activation and T cell infiltration, indicating that astrocytes actively participate in MS pathogenesis. Thus, Syncytin-1's proinflammatory properties in the nervous system demonstrate a novel pathogenic role for an endogenous retrovirus-encoded protein, which may serve as a target for future therapeutic intervention.