GlcNAc6ST-1 regulates sulfation of N-glycans and myelination in the peripheral nervous system

Takeshi Yoshimura,Mai Handa-Narumi,Hiroko Baba,Koichi Kato,Yoshihide Yamaguchi,Kenji Uchimura,Takako Koike,Jan Sedzik,Hirokazu Yagi,Kunio Kitamura,Kenji Kadomatsu,Nobuhiko Ohno,Kazuhiro Ikenaka,Bruce D Trapp,Akiko Hayashi

doi:10.1038/srep42257

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. P0 protein, 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.

Highlights

Rapid and efficient action potential propagation in vertebrates depends on axon ensheathment by a multilamellar membrane called myelin
In the present study we showed that GlcNAc6ST-1 almost exclusively catalyzes sulfation of N-glycans on glycoproteins in mouse peripheral nervous system (PNS) myelin (Fig. 2)
We further found that GlcNAc6ST-1 modulates myelination and myelinated axonal survival in the mouse PNS (Figs 3,4,5 and 6)

Summary

Introduction

Rapid and efficient action potential propagation in vertebrates depends on axon ensheathment by a multilamellar membrane called myelin. Degeneration of demyelinated axons is a major cause of permanent neurological disability in primary human myelin diseases[6]. The precise structures and roles of glycans on myelin glycoproteins remain largely unknown. Complete sulfated glycan structures as well as the function of myelin glycans remain largely unknown. We found that GlcNAc-6-O-sulfated N-glycans are highly conserved and abundant in PNS myelin among mammals. GlcNAc-6-O-sulfotransferase-1 (GlcNAc6ST-1) deficiency in mice resulted in a lack of sulfated N-glycans, and caused abnormal myelination and axonal degeneration in the PNS. These results suggest that the 6-O-sulfation of the GlcNAc residue by GlcNAc6ST-1 is critical for normal PNS myelination

Methods

Results

Conclusion