N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration.
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.
Lee
Sung-Uk
SU
Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697.
Grigorian
Ani
A
Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697.
Pawling
Judy
J
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G1X5, Canada.
Chen
I-Ju
IJ
Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697.
Gao
Guoyan
G
Department of Neurology, University of California, Irvine, California, 92697.
Mozaffar
Tahseen
T
Department of Neurology, University of California, Irvine, California, 92697.
McKerlie
Colin
C
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G1X5, Canada.
Demetriou
Michael
M
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G1X5, Canada; Department of Neurology, University of California, Irvine, California, 92697. Electronic address: mdemetri@uci.edu.
D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism; D002469:Cell Separation; D003711:Demyelinating Diseases / Q000473:pathology; D005434:Flow Cytometry; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009103:Multiple Sclerosis / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry*; D013601:T-Lymphocytes / Q000378:metabolism
D011134:Polysaccharides