N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation

J Biol Chem. 2020 Dec 18;295(51):17413-17424. doi: 10.1074/jbc.RA120.015595.

Abstract

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.

Keywords: N-acetylglucosamine; N-glycan branching; N-linked glycosylation; metabolism; multiple sclerosis; myelin; myelin repair; myelination; oligodendrocyte; oligodendrocyte precursor cell; oligodendrocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / administration & dosage
  • Acetylglucosamine / pharmacology*
  • Acetylglucosamine / therapeutic use
  • Administration, Oral
  • Animals
  • Biomarkers / metabolism
  • Cell Differentiation*
  • Demyelinating Diseases / drug therapy
  • Endocytosis
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myelin Sheath / metabolism*
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Oligodendrocyte Precursor Cells / cytology*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Signal Transduction

Substances

  • Biomarkers
  • Neuroprotective Agents
  • Receptor, Platelet-Derived Growth Factor alpha
  • Acetylglucosamine