Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis

B. Kornek, M. K. Storch, J. Bauer, A. Djamshidian, R. Weissert, E. Wallstroem, A. Stefferl, F. Zimprich, T. Olsson, Christopher Linington, M. Schmidbauer, H. Lassmann

    Research output: Contribution to journalArticle

    154 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1114-1124
    Number of pages10
    JournalBrain
    Volume124
    DOIs
    Publication statusPublished - 2001

    Keywords

    • voltage-gated calcium channels
    • multiple sclerosis
    • experimental autoimmune encephalomyelitis
    • axon degeneration
    • CENTRAL-NERVOUS-SYSTEM
    • AMYLOID PRECURSOR PROTEIN
    • SPINAL-CORD ATROPHY
    • CNS WHITE-MATTER
    • NA+-CA2+ EXCHANGER
    • ANOXIC INJURY
    • DISEASE PROGRESSION
    • HYPOINTENSE LESIONS
    • SODIUM-CHANNELS
    • CA2+ CHANNELS

    Cite this

    Kornek, B., Storch, M. K., Bauer, J., Djamshidian, A., Weissert, R., Wallstroem, E., ... Lassmann, H. (2001). Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain, 124, 1114-1124. https://doi.org/10.1093/brain/124.6.1114

    Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. / Kornek, B.; Storch, M. K.; Bauer, J.; Djamshidian, A.; Weissert, R.; Wallstroem, E.; Stefferl, A.; Zimprich, F.; Olsson, T.; Linington, Christopher; Schmidbauer, M.; Lassmann, H.

    In: Brain, Vol. 124, 2001, p. 1114-1124.

    Research output: Contribution to journalArticle

    Kornek, B, Storch, MK, Bauer, J, Djamshidian, A, Weissert, R, Wallstroem, E, Stefferl, A, Zimprich, F, Olsson, T, Linington, C, Schmidbauer, M & Lassmann, H 2001, 'Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis', Brain, vol. 124, pp. 1114-1124. https://doi.org/10.1093/brain/124.6.1114
    Kornek, B. ; Storch, M. K. ; Bauer, J. ; Djamshidian, A. ; Weissert, R. ; Wallstroem, E. ; Stefferl, A. ; Zimprich, F. ; Olsson, T. ; Linington, Christopher ; Schmidbauer, M. ; Lassmann, H. / Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. In: Brain. 2001 ; Vol. 124. pp. 1114-1124.
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    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.",
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    T1 - Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis

    AU - Kornek, B.

    AU - Storch, M. K.

    AU - Bauer, J.

    AU - Djamshidian, A.

    AU - Weissert, R.

    AU - Wallstroem, E.

    AU - Stefferl, A.

    AU - Zimprich, F.

    AU - Olsson, T.

    AU - Linington, Christopher

    AU - Schmidbauer, M.

    AU - Lassmann, H.

    PY - 2001

    Y1 - 2001

    N2 - 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.

    AB - 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.

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    KW - multiple sclerosis

    KW - experimental autoimmune encephalomyelitis

    KW - axon degeneration

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    KW - SPINAL-CORD ATROPHY

    KW - CNS WHITE-MATTER

    KW - NA+-CA2+ EXCHANGER

    KW - ANOXIC INJURY

    KW - DISEASE PROGRESSION

    KW - HYPOINTENSE LESIONS

    KW - SODIUM-CHANNELS

    KW - CA2+ CHANNELS

    U2 - 10.1093/brain/124.6.1114

    DO - 10.1093/brain/124.6.1114

    M3 - Article

    VL - 124

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    EP - 1124

    JO - Brain

    JF - Brain

    SN - 0006-8950

    ER -