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

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, Katherine A. Siminovitch, K. George Chandy, Zhaoxia Yu, James W. Dennis and Michael Demetriou ()
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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
Erin Walker: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Katherine A. Siminovitch: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
K. George Chandy: University of California
Zhaoxia Yu: University of California
James W. Dennis: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Michael Demetriou: University of California

Nature Communications, 2011, vol. 2, issue 1, 1-13

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1333

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