title: Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis.
abstract: Saltatory conduction in the nervous system is enabled through the intimate association between the leading edge of the myelin sheath and the axonal membrane to demarcate the node of Ranvier. The 186 kDa neuron specific isoform of the adhesion molecule neurofascin (Nfasc186) is required for the clustering of voltage gated Na+ channels at the node, whilst the 155 kDa glial specific isoform (Nfasc155) is required for the assembly of correct paranodal junctions. In order to understand the relationship between these vital structures and how they are affected in multiple sclerosis we have examined the expression of Nfasc155 and Nfasc186 in areas of inflammation, demyelination and remyelination from post-mortem brains. Fourteen cases of neuropathologically confirmed multiple sclerosis (8 female and 6 male; post-mortem delay 7-24 h; age 37-77 years; and disease duration 15-40 years), comprising 20 tissue blocks with 32 demyelinating or remyelinating lesions, were used in this study. A significant early alteration in Nfasc155+ paranodal structures occurs within and adjacent to actively demyelinating white matter lesions that are associated with damaged axons. Shaker-type Kv1.2 channels, normally located distally to the paranode, overlapped with the disrupted Nfasc155+ structures. In the absence of Nfasc155, Kv1.2 channels abutted normally clustered Nfasc186+ nodes, indicating that complete disruption of the paranodal structure and movement of Kv1.2 channels precede alterations at the node itself. Within areas of partial remyelination, a number of atypical triple-Nfasc155+ structures were noted that may represent transient oligodendrocyte-axonal contacts during the process of myelin repair or aberrant interactions. Within shadow plaques discretely clustered Na+v, Nfasc186+ and Nfasc155+ domains indicated the restoration of normal nodal architecture. The alterations in oligodendrocyte Nfasc155 expression that accompany inflammation and demyelination suggest an ongoing disruption to the axonal-oligodendrocyte complex within newly forming as well as established lesions in multiple sclerosis, resulting in destruction of the Nfasc186+/Na+v nodal complex vital to successful fast neurotransmission in the CNS.
authors.affiliation: Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health Imperial College Faculty of Medicine, Charing Cross Hospital Campus, London, UK.
authors.forename: O W
authors.initials: OW
authors.lastname: Howell
authors.forename: A
authors.initials: A
authors.lastname: Palser
authors.forename: A
authors.initials: A
authors.lastname: Polito
authors.forename: S
authors.initials: S
authors.lastname: Melrose
authors.forename: B
authors.initials: B
authors.lastname: Zonta
authors.forename: C
authors.initials: C
authors.lastname: Scheiermann
authors.forename: A J
authors.initials: AJ
authors.lastname: Vora
authors.forename: P J
authors.initials: PJ
authors.lastname: Brophy
authors.forename: R
authors.initials: R
authors.lastname: Reynolds
mesh_terms: D000328:Adult; D000368:Aged; D001344:Autopsy; D001369:Axons / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D001923:Brain Chemistry; D015815:Cell Adhesion Molecules / Q000032:analysis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology*; D009413:Nerve Fibers, Myelinated / Q000737:chemistry / Q000473:pathology* / Q000502:physiology; D009414:Nerve Growth Factors / Q000032:analysis*; D009836:Oligodendroglia / Q000473:pathology; D015221:Potassium Channels; D020033:Protein Isoforms / Q000032:analysis; D011901:Ranvier's Nodes / Q000473:pathology
chemical_list: D015815:Cell Adhesion Molecules; C054305:NFASC protein, human; D009414:Nerve Growth Factors; D015221:Potassium Channels; D020033:Protein Isoforms