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J. Biol. Chem., Vol. 282, Issue 46, 33725-33734, November 16, 2007

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N-Glycan Processing Deficiency Promotes Spontaneous Inflammatory Demyelination and Neurodegeneration^*

Sung-Uk Lee¹, Ani Grigorian¹, Judy Pawling, I-Ju Chen, Guoyan Gao^¶, Tahseen Mozaffar^¶, Colin McKerlie, and Michael Demetriou^¶2

From the Departments of ^¶Neurology and Microbiology and Molecular Genetics, University of California, Irvine, California 92697 and the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G1X5, Canada

Multiple sclerosis (MS) is characterized by inflammatory demyelination of axons and neurodegeneration, the latter inadequately modeled in experimental autoimmune encephalomyelitis (EAE). Susceptibility of inbred mouse strains to EAE is in part determined by major histocompatibility complex haplotype; however, other molecular mechanisms remain elusive. Galectins bind GlcNAc-branched N-glycans attached to surface glycoproteins, forming a molecular lattice that restricts lateral movement and endocytosis of glycoproteins. GlcNAc branching negatively regulates T cell activity and autoimmunity, and when absent in neurons, induces apoptosis in vivo in young adult mice. We find that EAE susceptible mouse strains PL/J, SJL, and NOD have reduced GlcNAc branching. PL/J mice display the lowest levels, partial deficiencies in N-acetylglucosaminyltransferase I, II, and V (i.e. Mgat1, -2, and -5), T cell hyperactivity and spontaneous late onset inflammatory demyelination and neurodegeneration; phenotypes markedly enhanced by Mgat5^+/- and Mgat5^-/- backgrounds in a gene dose-dependent manner. Spontaneous disease is transferable and characterized by progressive paralysis, tremor, dystonia, neuronophagia, and axonal damage in both demyelinated lesions and normal white matter, phenocopying progressive MS. Our data identify hypomorphic Golgi processing as an inherited trait that determines susceptibility to EAE, provides a unique spontaneous model of MS, and suggests GlcNAc-branching deficiency may promote T cell-mediated demyelination and neurodegeneration in MS.

Received for publication, June 12, 2007 , and in revised form, July 30, 2007.

^* This work was supported by grants from the National Multiple Sclerosis Society, Juvenile Diabetes Research Foundation, Wadsworth Foundation, and the United States NIAID, National Institutes of Health (to M. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1, Figs. S1-S6, and Video 1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Depts. of Neurology and Microbiology & Molecular Genetics, University of California, 250 Sprague Hall, Irvine, CA 92697. Tel.: 949-824-9775; Fax: 949-824-9847; E-mail: mdemetri{at}uci.edu.

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