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N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration

Sung-Uk Lee1, Ani Grigorian1, Judy Pawling2

  • 1Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697.

The Journal of Biological Chemistry
|September 15, 2007
PubMed

Insights

Reduced GlcNAc branching in mice leads to T cell hyperactivity, spontaneous demyelination, and neurodegeneration, modeling progressive multiple sclerosis (MS). This suggests a link between Golgi processing defects and MS susceptibility.

Area of Science:

  • Neuroimmunology
  • Glycobiology
  • Neurodegeneration

Background:

  • Multiple sclerosis (MS) involves inflammation, demyelination, and neurodegeneration, with experimental autoimmune encephalomyelitis (EAE) inadequately modeling the latter.
  • Mouse strain susceptibility to EAE is linked to MHC haplotype, but other molecular factors are unclear.
  • Galectins and N-glycan branching influence T cell activity and neuronal health.

Purpose of the Study:

  • Investigate the role of N-glycan branching in EAE susceptibility and MS pathogenesis.
  • Identify molecular mechanisms underlying spontaneous demyelination and neurodegeneration in mice.
  • Establish a novel spontaneous mouse model for progressive multiple sclerosis.

Main Methods:

  • Compared GlcNAc branching levels in EAE-susceptible mouse strains.
  • Analyzed N-acetylglucosaminyltransferase (Mgat) gene expression and activity.
  • Studied spontaneous demyelination and neurodegeneration in PL/J mice, including genetic manipulation of Mgat5.
  • Assessed disease transferability and characterized pathological features.

Main Results:

  • EAE-susceptible strains (PL/J, SJL, NOD) showed reduced GlcNAc branching.
  • PL/J mice exhibited lowest branching, Mgat1/2/5 deficiencies, T cell hyperactivity, and spontaneous demyelination/neurodegeneration.
  • Mgat5 deficiency exacerbated spontaneous disease in a gene-dose-dependent manner.
  • Spontaneous disease was transferable and phenocopied progressive MS, including axonal damage.

Conclusions:

  • Hypomorphic Golgi processing (reduced GlcNAc branching) is an inherited trait determining EAE susceptibility.
  • This study provides a unique spontaneous model for progressive MS.
  • GlcNAc-branching deficiency may drive T cell-mediated demyelination and neurodegeneration in MS.

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