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Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice

McGonigal, R. and Rowan, E.G. and Greenshields, K.N and Halstead, S. and Humphreys, P.D and Rother, R.P and Furukawa, K. and Willison, H.J. (2010) Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain, 133 (7). pp. 1944-1960. ISSN 0006-8950

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    Abstract

    The motor axonal variant of Guillain-Barré syndrome is associated with anti-GD1a immunoglobulin antibodies, which are believed to be the pathogenic factor. In previous studies we have demonstrated the motor terminal to be a vulnerable site. Here we show both in vivo and ex vivo, that nodes of Ranvier in intramuscular motor nerve bundles are also targeted by anti-GD1a antibody in a gradient-dependent manner, with greatest vulnerability at distal nodes. Complement deposition is associated with prominent nodal injury as monitored with electrophysiological recordings and fluorescence microscopy. Complete loss of nodal protein staining, including voltage-gated sodium channels and ankyrin G, occurs and is completely protected by both complement and calpain inhibition, although the latter provides no protection against electrophysiological dysfunction. In ex vivo motor and sensory nerve trunk preparations, antibody deposits are only observed in experimentally desheathed nerves, which are thereby rendered susceptible to complement-dependent morphological disruption, nodal protein loss and reduced electrical activity of the axon. These studies provide a detailed mechanism by which loss of axonal conduction can occur in a distal dominant pattern as observed in a proportion of patients with motor axonal Guillain-Barré syndrome, and also provide an explanation for the occurrence of rapid recovery from complete paralysis and electrophysiological in-excitability. The study also identifies therapeutic approaches in which nodal architecture can be preserved.

    Item type: Article
    ID code: 18561
    Notes: Also submitted to: Brain Research. This is a variant record V: 18561
    Keywords: anti-gd1a antibodies, antibodies, activate complement, calpain, distal motor nodes, ranvier, mice, Neuroscience. Biological psychiatry. Neuropsychiatry, Therapeutics. Pharmacology, Clinical Neurology
    Subjects: Medicine > Internal medicine > Neuroscience. Biological psychiatry. Neuropsychiatry
    Medicine > Therapeutics. Pharmacology
    Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Related URLs:
    Depositing user: Dr EG Rowan
    Date Deposited: 07 Apr 2010 11:59
    Last modified: 26 Apr 2014 03:49
    URI: http://strathprints.strath.ac.uk/id/eprint/18561

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