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

Nature Neuroscience volume 7, pages 10881095 (2004) | Download Citation

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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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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).

Author information

Affiliations

  1. Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.

    • Joseph M Antony
    • , Guido van Marle
    • , Voon Wee Yong
    •  & Christopher Power
  2. Department of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506-0055, USA.

    • Wycliffe Opii
    •  & D Allan Butterfield
  3. UMR CNRS-bioMerieux, IFR128 BioSciences Lyon-Gerland, Ecole Normale Superieure de Lyon, Lyon 69364, France.

    • François Mallet
  4. Department of Pharmacology & Therapeutics, University of Calgary, Calgary, Alberta T2N 4N1, Canada.

    • John L Wallace
  5. Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, UK.

    • Robert M Deacon
  6. Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2B7, Canada.

    • Kenneth Warren

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Christopher Power.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Syncytin co-localization with phagocytic macrophages in acute demyelinating lesions.

  2. 2.

    Supplementary Fig. 2

    HERV env mRNA is induced in monocytes and astrocytes.

  3. 3.

    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.

  4. 4.

    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.

  5. 5.

    Supplementary Fig. 5

    Syncytin does not cause neuronal toxicity.

  6. 6.

    Supplementary Fig. 6

    Syncytin-mediated rat oligodendrocyte toxicity was prevented by anti-oxidants in a dose-dependent manner.

  7. 7.

    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.

  8. 8.

    Supplementary Fig. 8

    Syncytin induces microgliosis in mice brain.

  9. 9.

    Supplementary Fig. 9

    Syncytin-induced neurobehavioral changes in mice.

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DOI

https://doi.org/10.1038/nn1319

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