Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis.
Saltatory conduction in myelinated fibres depends on the specific molecular organization of highly specialized axonal domains at the node of Ranvier, the paranodal and the juxtaparanodal regions. Voltage-gated sodium channels (Na(v)) have been shown to be deployed along the naked demyelinated axon in experimental models of CNS demyelination and in multiple sclerosis lesions. Little is known about aggregation of nodal, paranodal and juxtaparanodal constituents during the repair process. We analysed by immunohistochemistry on free-floating sections from multiple sclerosis brains the expression and distribution of nodal (Na(v) channels), paranodal (paranodin/Caspr) and juxtaparanodal (K(v) channels and Caspr2) molecules in demyelinated and remyelinated lesions. Whereas in demyelinated lesions, paranodal and juxtaparanodal proteins are diffusely distributed on denuded axons, the distribution of Na(v) channels is heterogeneous, with a diffuse immunoreactivity but also few broad Na(v) channel aggregates in all demyelinated lesions. In contrast to the demyelinated plaques, all remyelinated lesions are characterized by the detection of aggregates of Na(v) channels, paranodin/Caspr, K(v) channels and Caspr2. Our data suggest that these aggregates precede remyelination, and that Na(v) channel aggregation is the initial event, followed by aggregation of paranodal and then juxtaparanodal axonal proteins. Remyelination takes place in multiple sclerosis tissue but myelin repair is often incomplete, and the reasons for this remyelination deficit are many. We suggest that a defect of Na(v) channel aggregation might be involved in the remyelination failure in demyelinated lesions with spared axons and oligodendroglial cells.
Coman
I
I
INSERM U711, Paris, France.
Aigrot
M S
MS
Seilhean
D
D
Reynolds
R
R
Girault
J A
JA
Zalc
B
B
Lubetzki
C
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D001369:Axons / Q000737:chemistry; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D015816:Cell Adhesion Molecules, Neuronal / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D018991:Myelin Proteolipid Protein / Q000032:analysis; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis; D015221:Potassium Channels / Q000032:analysis*; D015222:Sodium Channels / Q000032:analysis*
C491323:CNTNAP1 protein, human; C403049:CNTNAP2 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D015222:Sodium Channels