title: Differential modulation of the juxtaparanodal complex in Multiple Sclerosis.
abstract: Myelinated fibers are divided into discrete subdomains around the Nav-enriched nodes of Ranvier: the paranodes, where axoglial interactions occur, the juxtaparanodes, where voltage-gated potassium channels (VGKCs) are aggregated, and the internode. Perinodal changes have been reported in Multiple Sclerosis (MS) with functional consequences for the axon. Here we report on alterations of the 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. We show that the molecular organization and maintenance of juxtaparanodes is affected in lesions, perilesions and NAWM in chronic MS through protein and mRNA expression as well as immunohistochemistry. 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 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 of 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.
authors.affiliation: Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion, Greece; Institute of Molecular Biology & Biotechnology-FoRTH, Heraklion, Greece.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Kastriti
authors.affiliation: Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; Neurology Clinics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Irene
authors.initials: I
authors.lastname: Sargiannidou
authors.affiliation: Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; Neurology Clinics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Kleopas A
authors.initials: KA
authors.lastname: Kleopa
authors.affiliation: Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion, Greece; Institute of Molecular Biology & Biotechnology-FoRTH, Heraklion, Greece. Electronic address: karagoge@imbb.forth.gr.
authors.forename: Domna
authors.initials: D
authors.lastname: Karagogeos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001369:Axons / Q000378:metabolism; D016022:Case-Control Studies; D058969:Contactin 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011901:Ranvier's Nodes / Q000378:metabolism* / Q000473:pathology; D066127:White Matter / Q000378:metabolism* / Q000473:pathology
chemical_list: C548674:CNTN2 protein, human; C403049:CNTNAP2 protein, human; D058969:Contactin 2; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger
keywords: Chronic Multiple Sclerosis; Lesion; Normal-appearing white matter; Perilesion; TAG-1