N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration

J Biol Chem. 2007 Nov 16;282(46):33725-34. doi: 10.1074/jbc.M704839200. Epub 2007 Sep 13.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Axons / metabolism
  • Cell Separation
  • Demyelinating Diseases / pathology
  • Flow Cytometry
  • Inflammation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • Multiple Sclerosis / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurons / metabolism
  • Polysaccharides / chemistry*
  • T-Lymphocytes / metabolism


  • Polysaccharides