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Human endogenous retrovirus glycoprotein–mediated induction of redox reactants causes oligodendrocyte death and demyelination

Abstract

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 immunologically activated glia, although the consequences of HERV expression in the nervous system remain uncertain. Here, we report that the HERV-W encoded glycoprotein syncytin is upregulated in glial cells within acute demyelinating lesions of multiple sclerosis patients. Syncytin expression in astrocytes induced the release of redox reactants, which were cytotoxic to oligodendrocytes. Syncytin-mediated neuroinflammation and death of oligodendrocytes, with the ensuing neurobehavioral deficits, were prevented by the antioxidant ferulic acid in a mouse model of multiple sclerosis. Thus, syncytin's proinflammatory properties in the nervous system demonstrate a novel role for an endogenous retrovirus protein, which may be a target for therapeutic intervention.

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Figure 1: In vivo expression of HERV env.
Figure 2: Syncytin induces proinflammatory molecules in glial cells.
Figure 3: Syncytin causes oligodendrocyte damage and death.
Figure 4: Syncytin induces neuroinflammation and neurobehavioral abnormalities in mice.

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Acknowledgements

We thank P. Kubes, C. Hao and A. Clark for discussion; and C. Silva, A. Sullivan and A. Hood for technical assistance. J.M.A. holds a studentship from the Multiple Sclerosis Society of Canada (MSSC); G.v.M. is a Canadian Institutes of Health Research (CIHR)/Alberta Heritage Foundation for Medical Research (AHFMR) Fellow; V.W.Y. holds a Canada Research Chair (Tier 1) in neuroimmunology; J.L.W. is an AHFMR Scientist and C.P. is an AHFMR Scholar/CIHR Investigator. These studies were supported by the MSSC and CIHR Interdisciplinary Health Research Team (IHRT).

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Correspondence to Christopher Power.

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Supplementary information

Supplementary Fig. 1

Syncytin co-localization with phagocytic macrophages in acute demyelinating lesions. (PDF 1334 kb)

Supplementary Fig. 2

HERV env mRNA is induced in monocytes and astrocytes. (PDF 105 kb)

Supplementary Fig. 3

Relative fold change (RFC) in the levels of 4-HNE, a product of lipid peroxidation, was not significantly different in the conditioned medium from astrocytes (HFA) and macrophages (MDM) infected with SINrep5-syncytin compared to controls. (PDF 88 kb)

Supplementary Fig. 4

Conditioned media from human fetal astrocytes (HFA) infected with SINrep5-syncytin caused rat oligodendrocyte cytotoxicity and process retraction compared to conditioned media from SINrep5-EGFP-infected HFAs. (PDF 638 kb)

Supplementary Fig. 5

Syncytin does not cause neuronal toxicity. (PDF 140 kb)

Supplementary Fig. 6

Syncytin-mediated rat oligodendrocyte toxicity was prevented by anti-oxidants in a dose-dependent manner. (PDF 103 kb)

Supplementary Fig. 7

Treatment of astrocytes with NMDA and AMPA receptor agonists (MK-801 and NBQX respectively; 3 μM each), interferon-β (IFN-β; 100 U/ml) or glatiramer acetate (GA; 25 μg/ml) prior to infection with SINrep5-syncytin did not block oligodendrocyte cytotoxicity relative to untreated cells and in some instances appeared to exacerbate syncytin-induced cytotoxicity. (PDF 100 kb)

Supplementary Fig. 8

Syncytin induces microgliosis in mice brain. (PDF 1855 kb)

Supplementary Fig. 9

Syncytin-induced neurobehavioral changes in mice. (PDF 125 kb)

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Antony, J., van Marle, G., Opii, W. et al. Human endogenous retrovirus glycoprotein–mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat Neurosci 7, 1088–1095 (2004). https://doi.org/10.1038/nn1319

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