title: Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis.
abstract: Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are immune-mediated diseases of the CNS. They are characterized by widespread inflammation, demyelination and a variable degree of axonal loss. Recent magnetic resonance spectroscopy studies have indicated that axonal damage and loss are a reliable correlate of permanent clinical disability. Accordingly, neuropathological studies have confirmed the presence and timing of axonal injury in multiple sclerosis lesions. The mechanisms of axonal degeneration, however, are unclear. Since calcium influx may mediate axonal damage, we have studied the distribution of the pore-forming subunit of neuronal (N)-type voltage-gated calcium channels in the lesions of multiple sclerosis and EAE. We found that alpha(1B), the pore-forming subunit of N-type calcium channels, was accumulated within axons and axonal spheroids of actively demyelinating lesions. The axonal staining pattern of alpha(1B) was comparable with that of beta-amyloid precursor protein, which is an early and sensitive marker for disturbance of axonal transport. Importantly, within these injured axons, alpha(1B) was not only accumulated, but also integrated in the axoplasmic membrane, as shown by immune electron microscopy on the EAE material. This ectopic distribution of calcium channels in the axonal membrane may result in increased calcium influx, contributing to axonal degeneration, possibly via the activation of neutral proteases. Our data suggest that calcium influx through voltage-dependent calcium channels is one possible candidate mechanism for axonal degeneration in inflammatory demyelinating disorders.
authors.affiliation: Department of Neuroimmunology, Brain Research Institute, University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Kornek
authors.forename: M K
authors.initials: MK
authors.lastname: Storch
authors.forename: J
authors.initials: J
authors.lastname: Bauer
authors.forename: A
authors.initials: A
authors.lastname: Djamshidian
authors.forename: R
authors.initials: R
authors.lastname: Weissert
authors.forename: E
authors.initials: E
authors.lastname: Wallstroem
authors.forename: A
authors.initials: A
authors.lastname: Stefferl
authors.forename: F
authors.initials: F
authors.lastname: Zimprich
authors.forename: T
authors.initials: T
authors.lastname: Olsson
authors.forename: C
authors.initials: C
authors.lastname: Linington
authors.forename: M
authors.initials: M
authors.lastname: Schmidbauer
authors.forename: H
authors.initials: H
authors.lastname: Lassmann
mesh_terms: D000328:Adult; D000818:Animals; D001369:Axons / Q000473:pathology* / Q000648:ultrastructure; D001798:Blood Proteins / Q000032:analysis; D020864:Calcium Channels, N-Type / Q000032:analysis*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D006023:Glycoproteins; D006801:Humans; D007136:Immunoglobulins; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D013116:Spinal Cord / Q000473:pathology* / Q000503:physiopathology
chemical_list: C048566:A1BG protein, human; D001798:Blood Proteins; D020864:Calcium Channels, N-Type; D006023:Glycoproteins; D007136:Immunoglobulins