Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
Nature Communications, Article number: 334, doi:10.1038/ncomms1333
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. Michael Demetriou mdemetri at uci.edu
Received – 02 February 2011, Accepted – 04 May 2011, Published – 31 May 2011
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-? (IL7RA*C), interleukin-2 receptor-? (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.
Clipped from USA Today
“Looking at human cells, they find that a deficiency of Vitamin D3 (found in milk), variations in gene networks and individual cell tendencies to produce sugars related to glucosamine, combine to affect the type of immune cells produced by the body. Immune cells attack the nerves in multiple sclerosis and it appears that a combination of all these factors disrupts these cellular sugars, producing the wrong kind of immune cells, which may lead to the disease.
The study serves as a model for other complicated diseases, the study authors suggest. The production of cell sugars, or glycobiology, takes place independently of factors determined by genes, they note, which is why genome-wide studies of multiple sclerosis may not have picked up on this facet of the disease.”
Clipped from The Epoch Times
“The new findings show both vitamin D3 and GlcNAc can reverse the effects of the four genes, leading to normal addition of sugars to proteins.
"This suggests that oral vitamin D3 and GlcNAc may serve as the first therapy for MS that directly targets an underlying defect promoting disease," Demetriou said.”
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