Journal Article

pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis

Trapp, Bruce D., Jang, Jeong Ho, Gruchot, Joel, Volsko, Christina, Oldemeier, Lisa, Healy, Luke, Weyers, Vivien, Xu, Yu Kang T., Perron, Hervé, Kremer, David, Dutta, Ranjan, Hartung, Hans-Peter, Göttle, Peter, Küry, Patrick

2019

Overview

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

• Publisher: National Academy of Sciences
• Subject: Animals / Antibodies / Autoimmune diseases / Axons / Axons - metabolism / Axons - ultrastructure / Axons - virology / Biological Sciences / Brain / Cell Differentiation / Clinical Trials, Phase II as Topic / Coculture Techniques / Degeneration / Endogenous retroviruses / Endogenous Retroviruses - genetics / Endogenous Retroviruses - metabolism / Endogenous Retroviruses - pathogenicity / Female / Gene Expression / Humans / Lesions / Male / Microglia / Microglia - metabolism / Microglia - ultrastructure / Microglia - virology / Monocytes / Multiple sclerosis / Multiple Sclerosis - genetics / Multiple Sclerosis - metabolism / Multiple Sclerosis - pathology / Multiple Sclerosis - virology / Myelin Sheath - metabolism / Myelin Sheath - ultrastructure / Myelin Sheath - virology / Myelination / Myeloid cells / Neurodegeneration / Neurons - metabolism / Neurons - ultrastructure / Neurons - virology / Neuroprotection / Neuroscience / Neutralization / Phenotypes / PNAS Plus / Proteins / Rats / Rats, Wistar / Structural damage / Viral envelope proteins / Viral Envelope Proteins - genetics / Viral Envelope Proteins - metabolism