| Abstract |
The segregation of myelinated fibers into distinct domains around the node of Ranvier - the perinodal areas - is crucial for nervous system homeostasis and efficient nerve conduction. Perinodal areas are formed by axo-glial interactions, namely the interaction of molecules between the axon and the myelinating glia. In a variety of demyelinating pathologies including multiple sclerosis, the molecular architecture of the myelinated fiber is disrupted, leading to axonal degeneration.
In this study we have analyzed the alterations of TAG-1, Caspr2 and voltage-gated potassium channels (VGKCs), forming the juxtaparanodal tripartite complex, in relation to adjacent paranodal and nodal molecules, in two different models of CNS demyelination, the experimental autoimmune encephalomyelitis (EAE) and the cuprizone model of toxic demyelination.
We found extensive alterations of the juxtaparanodal molecular architecture under de- and remyelinating conditions. Inflammation alone was sufficient to disrupt the borders between the domains leading to the diffusion of juxtaparanodal components to the adjacent paranodal area. EAE induction and cuprizone-induced demyelination resulted initially in paranodal domain elongation with subsequent diffusion of the juxtaparanodal components towards the paranodal and the internodal domains. At later stages, with decreasing inflammation and spontaneous remyelination there was a partial restoration of the paranodal domain but not sufficient re-organization of the juxtaparanodes. The latter were re-formed only when complete remyelination was allowed in the cuprizone model, indicating that juxtaparanodal domain re-organization is a later event that may remain incomplete in a hostile inflammatory milieu.
We additionally examined for the first time the role of the cell adhesion molecule TAG-1 during CNS de- and remyelination, using the cuprizone model of toxic demyelination. The lack of TAG-1 protein from the myelinated fiber led to irregular oligodendroglial dynamics during demyelination with the TAG-1 mutant animals exhibiting delayed demyelination. In addition, upon CNS remyelination the lack of TAG-1 protein revealed a novel, TAG-1 independent mechanism of VGKC clustering at the juxtaparanodal area, probably as a protective mechanism against extensive damage
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Μελέτη της οργάνωσης των περικομβικών περιοχών των εμμύελων ινών σε συνθήκες απομυελίνωσης και επαναμυελίνωσης
