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Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis

Author

Listed:
  • Haik Mkhikian

    (University of California)

  • Ani Grigorian

    (University of California)

  • Carey F. Li

    (University of California)

  • Hung-Lin Chen

    (University of California)

  • Barbara Newton

    (University of California)

  • Raymond W. Zhou

    (University of California)

  • Christine Beeton

    (University of California)

  • Sevan Torossian

    (University of California)

  • Gevork Grikor Tatarian

    (University of California)

  • Sung-Uk Lee

    (University of California)

  • Ken Lau

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital
    University of Toronto)

  • Erin Walker

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital
    University of Toronto)

  • Katherine A. Siminovitch

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital
    University of Toronto)

  • K. George Chandy

    (University of California)

  • Zhaoxia Yu

    (University of California)

  • James W. Dennis

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital
    University of Toronto)

  • Michael Demetriou

    (University of California
    University of California)

Abstract

How environmental factors combine with genetic risk at the molecular level to promote complex trait diseases such as multiple sclerosis (MS) is largely unknown. In mice, N-glycan branching by the Golgi enzymes Mgat1 and/or Mgat5 prevents T cell hyperactivity, cytotoxic T-lymphocyte antigen 4 (CTLA-4) endocytosis, spontaneous inflammatory demyelination and neurodegeneration, the latter pathologies characteristic of MS. Here we show that MS risk modulators converge to alter N-glycosylation and/or CTLA-4 surface retention conditional on metabolism and vitamin D3, including genetic variants in interleukin-7 receptor-α (IL7RA*C), interleukin-2 receptor-α (IL2RA*T), MGAT1 (IVAVT−T) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IVAVT−T) and vitamin D3, optimizing branching and mitigating MS risk when combined with enhanced CTLA-4 N-glycosylation by CTLA-4 Thr17. Our data suggest a molecular mechanism in MS whereby multiple environmental and genetic inputs lead to dysregulation of a final common pathway, namely N-glycosylation.

Suggested Citation

  • Haik Mkhikian & Ani Grigorian & Carey F. Li & Hung-Lin Chen & Barbara Newton & Raymond W. Zhou & Christine Beeton & Sevan Torossian & Gevork Grikor Tatarian & Sung-Uk Lee & Ken Lau & Erin Walker & Kat, 2011. "Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis," Nature Communications, Nature, vol. 2(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1333
    DOI: 10.1038/ncomms1333
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    Cited by:

    1. Guy Werlen & Mei-Ling Li & Luca Tottone & Victoria da Silva-Diz & Xiaoyang Su & Daniel Herranz & Estela Jacinto, 2022. "Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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