title: Loss of branched O-mannosyl glycans in astrocytes accelerates remyelination.
abstract: In demyelinating diseases such as multiple sclerosis, a critical problem is failure of remyelination, which is important for protecting axons against degeneration and restoring conduction deficits. However, the underlying mechanism of demyelination/remyelination remains unclear. N-acetylglucosaminyltransferase-IX (GnT-IX; also known as GnT-Vb) is a brain-specific glycosyltransferase that catalyzes the branched formation of O-mannosyl glycan structures. O-Mannosylation of α-dystroglycan is critical for its function as an extracellular matrix receptor, but the biological significance of its branched structures, which are exclusively found in the brain, is unclear. In this study, we found that GnT-IX formed branched O-mannosyl glycans on receptor protein tyrosine phosphatase β (RPTPβ) in vivo. Since RPTPβ is thought to play a regulatory role in demyelinating diseases, GnT-IX-deficient mice were subjected to cuprizone-induced demyelination. Cuprizone feeding for 8 weeks gradually promoted demyelination in wild-type mice. In GnT-IX-deficient mice, the myelin content in the corpus callosum was reduced after 4 weeks of treatment, but markedly increased at 8 weeks, suggesting enhanced remyelination under GnT-IX deficiency. Furthermore, astrocyte activation in the corpus callosum of GnT-IX-deficient mice was significantly attenuated, and an oligodendrocyte cell lineage analysis indicated that more oligodendrocyte precursor cells differentiated into mature oligodendrocytes. Together, branched O-mannosyl glycans in the corpus callosum in the brain are a necessary component of remyelination inhibition in the cuprizone-induced demyelination model, suggesting that modulation of O-mannosyl glycans is a likely candidate for therapeutic strategies.
authors.affiliation: Disease Glycomics Team, Systems Glycobiology Research Group, RIKEN-MAX Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, RIKEN, Saitama 351-0198, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kanekiyo
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Inamori
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kitazume
authors.forename: Keiko
authors.initials: K
authors.lastname: Sato
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kizuka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Korekane
authors.forename: Ichiro
authors.initials: I
authors.lastname: Matsuo
authors.forename: Koichi
authors.initials: K
authors.lastname: Honke
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
mesh_terms: D000367:Age Factors; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D033922:Clathrin Heavy Chains / Q000378:metabolism; D003337:Corpus Callosum / Q000473:pathology; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D011134:Polysaccharides / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D009419:Nerve Tissue Proteins; D011134:Polysaccharides; D033922:Clathrin Heavy Chains; D003471:Cuprizone; D017351:N-Acetylglucosaminyltransferases; C510765:N-acetylglucosaminyltransferase IX, mouse; C516887:Ptprb protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3