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

Nat Commun. 2011;2:334. doi: 10.1038/ncomms1333.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • CTLA-4 Antigen
  • Case-Control Studies
  • Cholecalciferol / metabolism
  • Cohort Studies
  • Down-Regulation
  • Female
  • Genetic Variation
  • Glycosylation
  • Haplotypes
  • Humans
  • Male
  • Mice
  • Mice, Inbred Strains
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / metabolism
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism
  • Receptors, Interleukin-2 / genetics
  • Receptors, Interleukin-7 / genetics
  • Risk Factors
  • Signal Transduction
  • Sunlight

Substances

  • Antigens, CD
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Receptors, Interleukin-2
  • Receptors, Interleukin-7
  • Cholecalciferol
  • MGAT1 protein, human
  • N-Acetylglucosaminyltransferases