Gangliosides contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibers.
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.
Susuki
Keiichiro
K
Department of Neurology, Dokkyo Medical University School of Medicine, Kitakobayashi 880, Mibu, Shimotsuga, Tochigi 321-0293, Japan. ksusuki@uchc.edu
Baba
Hiroko
H
Tohyama
Koujiro
K
Kanai
Kazuaki
K
Kuwabara
Satoshi
S
Hirata
Koichi
K
Furukawa
Keiko
K
Furukawa
Koichi
K
Rasband
Matthew N
MN
Yuki
Nobuhiro
N
D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001369:Axons / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D005732:Gangliosides / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology; D009431:Neural Conduction / Q000235:genetics; D016900:Neurofilament Proteins / Q000378:metabolism; D010525:Peripheral Nerves / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011129:Polyradiculoneuropathy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015221:Potassium Channels / Q000378:metabolism; D011901:Ranvier's Nodes / Q000378:metabolism* / Q000473:pathology; D012583:Schwann Cells / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D013126:Spinal Nerve Roots / Q000378:metabolism / Q000473:pathology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D005732:Gangliosides; D007473:Ion Channels; D016900:Neurofilament Proteins; D015221:Potassium Channels; D015222:Sodium Channels; C064020:ganglioside GD1alpha; D005677:G(M1) Ganglioside