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

  • Author(s): Mkhikian, Haik
  • Grigorian, Ani
  • Li, Carey F
  • Chen, Hung-Lin
  • Newton, Barbara
  • Zhou, Raymond W
  • Beeton, Christine
  • Torossian, Sevan
  • Tatarian, Gevork Grikor
  • Lee, Sung-Uk
  • Lau, Ken
  • Walker, Erin
  • Siminovitch, Katherine A
  • Chandy, K George
  • Yu, Zhaoxia
  • Dennis, James W
  • Demetriou, Michael
  • et al.
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 D(3), including genetic variants in interleukin-7 receptor-α (IL7RA*C), interleukin-2 receptor-α (IL2RA*T), MGAT1 (IV(A)V(T-T)) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IV(A)V(T-T)) and vitamin D(3), 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.

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