Disruption of neurofascin and gliomedin at nodes of Ranvier precedes demyelination in experimental allergic neuritis

Brain. 2009 Jan;132(Pt 1):260-73. doi: 10.1093/brain/awn281. Epub 2008 Oct 25.

Abstract

High densities of voltage-gated sodium (Nav) channels at nodes of Ranvier enable the rapid regeneration and propagation of the action potentials along myelinated axons. In demyelinating pathologies, myelin alterations lead to conduction slowing and even to conduction block. In order to unravel the mechanisms of conduction failure in inflammatory demyelinating diseases, we have examined two models of Guillain-Barré syndrome: the experimental allergic neuritis induced in the Lewis rat by immunization against peripheral myelin (EAN-PM) and against a neuritogenic P2 peptide (EAN-P2). We found that Nav channel clusters were disrupted at EAN-PM nodes. Neurofascin and gliomedin, two cell adhesion molecules involved with aggregating Nav channels at nodes, were selectively affected prior to demyelination in EAN-PM, indicating that degradation of the axo-glial unit initiated node alteration. This was associated with autoantibodies to neurofascin and gliomedin. Node disruption was, however, independent from complement deposition at nodes, and deposits of the terminal complement complex (C5b-9) were found on the external surface of Schwann cells in EAN-PM. In these animals, the paranodal junctions were also affected and Kv1 channels, which are normally juxtaparanodal, were found dispersed at nodes and paranodes. Altogether, these alterations were associated with conduction deficits in EAN-PM ventral spinal roots. EAN-P2 animals also exhibited inflammatory demyelination, but did not show alteration in nodal clusters or autoantibodies. Our results highlighted the complex mechanisms underlying conduction abnormalities in demyelinating disorders, and unraveled neurofascin and gliomedin as two novel immune targets in experimental allergic neuritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / immunology
  • Cell Adhesion Molecules / immunology
  • Cell Adhesion Molecules / physiology*
  • Cell Adhesion Molecules, Neuronal / immunology
  • Cell Adhesion Molecules, Neuronal / physiology*
  • Complement Membrane Attack Complex / metabolism
  • Disease Models, Animal
  • Guillain-Barre Syndrome / immunology
  • Guillain-Barre Syndrome / metabolism*
  • Guillain-Barre Syndrome / pathology
  • Male
  • Nerve Growth Factors / immunology
  • Nerve Growth Factors / physiology*
  • Neural Conduction
  • Neuritis, Autoimmune, Experimental / immunology
  • Neuritis, Autoimmune, Experimental / metabolism*
  • Neuritis, Autoimmune, Experimental / pathology
  • Potassium Channels, Voltage-Gated
  • Ranvier's Nodes / metabolism*
  • Rats
  • Rats, Inbred Lew
  • Schwann Cells / immunology
  • Sodium Channels / physiology
  • Spinal Nerve Roots / physiopathology

Substances

  • Autoantibodies
  • Cell Adhesion Molecules
  • Cell Adhesion Molecules, Neuronal
  • Complement Membrane Attack Complex
  • Nerve Growth Factors
  • Nfasc protein, rat
  • Potassium Channels, Voltage-Gated
  • Sodium Channels
  • gliomedin, rat