Transgenic expression of the HERV-W envelope protein leads to polarized glial cell populations and a neurodegenerative environment

• DOI: 10.1073/pnas.2308187120
• Publication Date: 2023-09-11T19:07:41Z
• Authors: Joel Gruchot; Isabel Lewen; Michael Dietrich; Laura Reiche; Mustafa Sindi; Christina Hecker; Felisa Herrero; Benjamin Charvet; Ulrike Weber-Stad...; Hans-Peter Hartung; Philipp Albrecht; Hervé Perron; Urs Meyer; Patrick Küry
• Keywords: 1000 Multidisciplinary; Multidisciplinary; Multiple Sclerosis; Endogenous retrovirus; Multiple sclerosis; Neurodegeneration ; Myelin repair; Glia; Endogenous Retroviruses; 610 Medicine & health; 10079 Institute of Veterinary Pharmacology and Toxicology; Biological Sciences; 3. Good health; Animals, Genetically Modified; Multiple sclerosis; Mice; Glia; Endogenous retrovirus; Myelin repair; 570 Life sciences; biology; Humans; Animals; Neurodegeneration; Neuroglia; Myelin Sheath

The human endogenous retrovirus type W (HERV-W) has been identified and repeatedly confirmed as human-specific pathogenic entity affecting many cell types in multiple sclerosis (MS). Our recent contributions revealed the encoded envelope (ENV) protein to disturb myelin repair by interfering with oligodendroglial precursor differentiation and by polarizing microglial cells toward an axon-damage phenotype. Indirect proof of ENV’s antiregenerative and degenerative activities has been gathered recently in clinical trials using a neutralizing anti-ENV therapeutic antibody. Yet direct proof of its mode of action can only be presented here based on transgenic ENV expression in mice. Upon demyelination, we observed myelin repair deficits, neurotoxic microglia and astroglia, and increased axon degeneration. Experimental autoimmune encephalomyelitis activity progressed faster in mutant mice equally accompanied by activated glial cells. This study therefore provides direct evidence on HERV-W ENV’s contribution to the overall negative impact of this activated viral entity in MS.