Gangliosides contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibers

Authors

  • Keiichiro Susuki,

    Corresponding author
    1. Department of Neurology, Dokkyo Medical University School of Medicine, Tochigi, Japan
    2. Research Institute for Neuroimmunological Diseases, Dokkyo Medical University School of Medicine, Tochigi, Japan
    3. Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut
    • Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-3401, USA
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  • Hiroko Baba,

    1. Department of Molecular Neurobiology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
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  • Koujiro Tohyama,

    1. The Center for Electron Microscopy and Bio-Imaging Research, Laboratory for Nano-Neuroanatomy, Iwate Medical University, Morioka, Japan
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  • Kazuaki Kanai,

    1. Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
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  • Satoshi Kuwabara,

    1. Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
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  • Koichi Hirata,

    1. Department of Neurology, Dokkyo Medical University School of Medicine, Tochigi, Japan
    2. Research Institute for Neuroimmunological Diseases, Dokkyo Medical University School of Medicine, Tochigi, Japan
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  • Keiko Furukawa,

    1. Department of Biochemistry II, Nagoya University School of Medicine, Nagoya, Japan
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  • Koichi Furukawa,

    1. Department of Biochemistry II, Nagoya University School of Medicine, Nagoya, Japan
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  • Matthew N. Rasband,

    1. Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut
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  • Nobuhiro Yuki

    Corresponding author
    1. Department of Neurology, Dokkyo Medical University School of Medicine, Tochigi, Japan
    2. Research Institute for Neuroimmunological Diseases, Dokkyo Medical University School of Medicine, Tochigi, Japan
    • Department of Neurology and Research Institute for Neuroimmunological Diseases, Dokkyo Medical University School of Medicine, Kitakobayashi 880, Mibu, Shimotsuga, Tochigi, 321-0293, Japan
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Abstract

Paranodal axo-glial junctions are important for ion channel clustering and rapid action potential propagation in myelinated nerve fibers. Paranode formation depends on the cell adhesion molecules neurofascin (NF) 155 in glia, and a Caspr and contactin heterodimer in axons. We found that antibody to ganglioside GM1 labels paranodal regions. Autoantibodies to the gangliosides GM1 and GD1a are thought to disrupt nodes of Ranvier in peripheral motor nerves and cause Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness. To elucidate ganglioside function at and near nodes of Ranvier, we examined nodes in mice lacking gangliosides including GM1 and GD1a. In both peripheral and central nervous systems, some paranodal loops failed to attach to the axolemma, and immunostaining of Caspr and NF155 was attenuated. K+ channels at juxtaparanodes were mislocalized to paranodes, and nodal Na+ channel clusters were broadened. Abnormal immunostaining at paranodes became more prominent with age. Moreover, the defects were more prevalent in ventral than dorsal roots, and less frequent in mutant mice lacking the b-series gangliosides but with excess GM1 and GD1a. Electrophysiological studies revealed nerve conduction slowing and reduced nodal Na+ current in mutant peripheral motor nerves. The amounts of Caspr and NF155 in low density, detergent insoluble membrane fractions were reduced in mutant brains. These results indicate that gangliosides are lipid raft components that contribute to stability and maintenance of neuron-glia interactions at paranodes. © 2007 Wiley-Liss, Inc.

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