Page 5 - ISNI abstracts

International Joint Israel-Greek-Italian Neuroimmunological meeting Differential Modulation of the Juxtaparanodal Complex in Multiple Sclerosis M. Kastriti , I. Sargiannidou , K. A. Kleopa and D. Karagogeos 1,2 1,2 3 4,5 (1) Department of Basic Science, School of Medicine, University of Crete (2) IMBB-FORTH, Heraklion, Crete (3) Neuroscience Laboratory, and Neurology Clinics, The Cyprus Institute of Neurology and (4) Genetics, Nicosia, Cyprus Myelinated fibers are divided in discrete subdomains around the Nav-enriched nodes of Ranvier: the paranodes, where axoglial interactions occur, the juxtaparanodes, where voltage- gated potassium channels (VGKCs) are found in a complex with TAG-1 and Caspr2, and the internode. Perinodal changes have been reported in Multiple Sclerosis (MS) with functional consequences for the axon. Here we report on alterations of all three juxtaparanodal proteins TAG-1, Caspr2 and VGKCs in normal appearing white matter (NAWM), perilesion and chronic lesion areas in post-mortem white matter tissue from MS patients compared to control white matter. Using immunoblot and mRNA analysis as well as immunohistochemistry we found that the molecular organization and maintenance of juxtaparanodes is affected not only in lesions and perilesions but also in NAWM in chronic MS. The three molecules analyzed were differentially altered. TAG-1 clustering at juxtaparanodes was reduced in NAWM; TAG-1 and Caspr2 are diffused in perilesions and absent in lesion areas. VGKCs were the most susceptible of the three components as they were no longer enriched at juxtaparanodes either at the NAWM or the perilesion and demyelinated plaques. While the protein levels of the three molecules showed only a tendency for reduction in the plaques, there was a significant upregulation of Caspr2 mRNA in the lesions accompanied by a transcriptional increase of paranodal Caspr, indicating an axonal homeostatic mechanism. Our study is the first to comparatively analyze at the protein and molecular level the localization and expression of three components of the juxtaparanodal complex in chronic MS. Additionally, a phenotype of juxtaparanodal disruption is described for the first time in MS NAWM. 5