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

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.

The Pathogenesis of the Demyelinating Form of Guillain-Barre Syndrome (GBS): Proteo-peptidomic and Immunological Profiling of Physiological Fluids

“…Earlier, disorganization of the neurofascin and gliomedin aggregates was shown to precede demyelination in the experimental allergic neuritis induced in rat by immunization against peripheral myelin, thereby leading to the disruption of the nodal Na v ion channels and the subsequent conduction failure (62). Besides, antibodies to several proteins in the nodal area of the peripheral nerves -in particular, gliomedin, neurofascin, contactin (63,64), and moesin (65) -were found in the blood stream of some AIDP patients.…”

CIDP – the relevance of recent advances in Schwann cell/axonal neurobiology

“…Disease induced by peptides such as those derived from P2 or P0, results mainly in a T-cell response and affected animals show little demyelination pathologically whereas whole myelin induces a B-and T-cell response with abundant demyelination seen histologically (Taylor and Pollard, 2001). A recent study in EAN by Lonigro and Devaux (2009) in which EAN was induced by both PNM (EAN-PNM) or neuritogenic P2 peptide (EAN-P2) showed that in animals in which disease was induced by PNM but not in those with P2 peptide-induced disease, there was disruption of sodium channel clusters at the nodes which was associated with loss of the adhesion molecules gliomedin and neurofascin at the nodal region. Reduction in the density of these important adhesion molecules preceded loss of sodium channel clusters and paranodal demyelination and was accompanied by the presence of antibodies to gliomedin and neurofascin.…”

Neurofascin as a target for autoantibodies in peripheral neuropathies

“…8 Antibody binding at the node of Ranvier has been observed in EAN 9 and in patients with GBS and CIDP. 10 The neuronal isoform of neurofascin (NF)186 exposed at the node is crucial for sodium channel clustering, 11 while the glial isoform NF155 at the paranode is necessary for proper paranodal junction formation.…”

“…Previous studies of this P2 peptide-induced EAN model have demonstrated nerve infiltration by autoreactive T cells and macrophages, yet autoantibodies were not implicated. 9 We added anti-pan-NF mAbs into this disease setting and found that NF-targeting exacerbated disease. A similar observation was made in studies using a T-cell transfer EAN model in which addition of antimyelin antibodies greatly exacerbated disease.…”