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

Mkhikian H, Grigorian A, Li CF, Chen HL, Newton B, Zhou RW, Beeton C, Torossian S, Tatarian GG, Lee SU, Lau K, Walker E, Siminovitch KA, Chandy KG, Yu Z, Dennis JW, Demetriou M
Nat Commun. 2011 2: 334

PMID: 21629267 · PMCID: PMC3133923 · DOI:10.1038/ncomms1333

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.

MeSH Terms (22)

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

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