Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model
McGonigal, Rhona and Campbell, Clare I. and Barrie, Jennifer A. and Yao, Denggao and Cunningham, Madeleine E. and Crawford, Colin L. and Rinaldi, Simon and Rowan, Edward G. and Willison, Hugh J. (2022) Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model. Journal of Clinical Investigation, 132 (14). e158524. ISSN 0021-9738 (https://doi.org/10.1172/JCI158524)
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Abstract
In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti-GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axonal degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary bystander axonal degeneration following SC injury are unresolved. To investigate this, we generated glycosyltransferase-disrupted transgenic mice that express GM1 ganglioside either exclusively in neurons [GalNAcT-/-Tg(neuronal)] or glia [GalNAcT-/-Tg(glial)], thereby allowing anti-GM1 antibodies to solely target GM1 in either axonal or SC membranes, respectively. Myelinated-axon integrity in distal motor nerves was studied in transgenic mice exposed to anti-GM1 antibody and complement in ex vivo and in vivo injury paradigms. Axonal targeting induced catastrophic acute axonal disruption, as expected. When mice with GM1 in SC membranes were targeted, acute disruption of perisynaptic glia and SC membranes at nodes of Ranvier (NoRs) occurred. Following glial injury, axonal disruption at NoRs also developed subacutely, progressing to secondary axonal degeneration. These models differentiate the distinctly different axonopathic pathways under axonal and glial membrane targeting conditions, and provide insights into primary and secondary axonal injury, currently a major unsolved area in GBS research.
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Item type: Article ID code: 81292 Dates: DateEvent15 July 2022Published7 June 2022Published Online2 June 2022AcceptedSubjects: Medicine > Therapeutics. Pharmacology Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences Depositing user: Pure Administrator Date deposited: 29 Jun 2022 08:58 Last modified: 12 Dec 2024 13:25 URI: https://strathprints.strath.ac.uk/id/eprint/81292