title: GlcNAc6ST-1 regulates sulfation of N-glycans and myelination in the peripheral nervous system.
abstract: Highly specialized glial cells wrap axons with a multilayered myelin membrane in vertebrates. Myelin serves essential roles in the functioning of the nervous system. Axonal degeneration is the major cause of permanent neurological disability in primary myelin diseases. Many glycoproteins have been identified in myelin, and a lack of one myelin glycoprotein results in abnormal myelin structures in many cases. However, the roles of glycans on myelin glycoproteins remain poorly understood. Here, we report that sulfated N-glycans are involved in peripheral nervous system (PNS) myelination. PNS myelin glycoproteins contain highly abundant sulfated N-glycans. Major sulfated N-glycans were identified in both porcine and mouse PNS myelin, demonstrating that the 6-O-sulfation of N-acetylglucosamine (GlcNAc-6-O-sulfation) is highly conserved in PNS myelin between these species. P0protein, the most abundant glycoprotein in PNS myelin and mutations in which at the glycosylation site cause Charcot-Marie-Tooth neuropathy, has abundant GlcNAc-6-O-sulfated N-glycans. Mice deficient in N-acetylglucosamine-6-O-sulfotransferase-1 (GlcNAc6ST-1) failed to synthesize sulfated N-glycans and exhibited abnormal myelination and axonal degeneration in the PNS. Taken together, this study demonstrates that GlcNAc6ST-1 modulates PNS myelination and myelinated axonal survival through the GlcNAc-6-O-sulfation of N-glycans on glycoproteins. These findings may provide novel insights into the pathogenesis of peripheral neuropathy.
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.|Department of Physiological Sciences, School of Life Sciences, SOKENDAI (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Department of Molecular Neurobiology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.|Department of Physiological Sciences, School of Life Sciences, SOKENDAI (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Handa-Narumi
authors.affiliation: Department of Structural Biology and Biomolecular Engineering, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Yagi
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.|Department of Physiological Sciences, School of Life Sciences, SOKENDAI (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ohno
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Koike
authors.affiliation: Department of Molecular Neurobiology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Biochemistry, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466-8550, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Uchimura
authors.affiliation: Department of Biochemistry, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466-8550, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.|Department of Chemical Engineering and Technology, Protein Crystallization Facility, Royal Institute of Technology, KTH, Stockholm 10044, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Sedzik
authors.affiliation: Faculty of Health and Medical Care, Saitama Medical University, Hidaka, Saitama 350-1241, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Kitamura
authors.affiliation: Department of Structural Biology and Biomolecular Engineering, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan.|Institute for Molecular Science and Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Trapp
authors.affiliation: Department of Molecular Neurobiology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Baba
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.|Department of Physiological Sciences, School of Life Sciences, SOKENDAI (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikenaka
mesh_terms: D000818:Animals; D000838:Anions; D001369:Axons / Q000378:metabolism; D055162:Biocatalysis; D002490:Central Nervous System / Q000378:metabolism; D008322:Mammals; D018345:Mice, Knockout; D008954:Models, Biological; D009186:Myelin Sheath / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000378:metabolism*; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D012584:Sciatic Nerve / Q000201:enzymology / Q000473:pathology; D013431:Sulfates / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D000097811:Carbohydrate Sulfotransferases
chemical_list: D000838:Anions; D011134:Polysaccharides; D013431:Sulfates; D015238:Sulfotransferases; D000097811:Carbohydrate Sulfotransferases