Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model

McGonigal, R. , Campbell, C. I., Barrie, J. A., Yao, D., Cunningham, M. E. , Crawford, C. L., Rinaldi, S., Rowan, E. G. and Willison, H. 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. (doi: 10.1172/JCI158524) (PMID:35671105) (PMCID:PMC9282931)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Rowan, Dr Edward and Barrie, Mrs Jennifer and Crawford, Colin and Willison, Professor Hugh and Campbell, Ms Clare and McGonigal, Dr Rhona and Cunningham, Dr Madeleine and Rinaldi, Dr Simon and Yao, Dr Denggao
• Authors: McGonigal, R., Campbell, C. I., Barrie, J. A., Yao, D., Cunningham, M. E., Crawford, C. L., Rinaldi, S., Rowan, E. G., and Willison, H. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Journal of Clinical Investigation
• Publisher: Americal Society for Clinical Investigation
• ISSN: 0021-9738
• ISSN (Online): 1558-8238
• Published Online: 07 June 2022
• Copyright Holders: Copyright © 2022 McGonigal et al.
• First Published: First published in Journal of Clinical Investigation 132(14): e158524
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
165079		The structural and functional diversity of anti-glycolipid antibody repertoires and their nerve binding domains in human autoimmune neuropathy	Hugh Willison	Wellcome Trust (WELLCOTR)	092805/Z/10/Z	III - Immunology
173549		Pathophysiological factors in the diagnosis and treatment of the Guillain-Barre syndromes	Hugh Willison	Wellcome Trust (WELLCOTR)	202789/Z/16/Z	III - Immunology