Cunningham, M. E. , McGonigal, R. , Barrie, J. A., Campbell, C. I., Yao, D. and Willison, H. J. (2023) Axolemmal nanoruptures arising from paranodal membrane injury induce secondary axon degeneration in murine Guillain-Barré syndrome. Journal of the Peripheral Nervous System, 28(1), pp. 17-31. (doi: 10.1111/jns.12532) (PMID:36710500)
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Abstract
The major determinant of poor outcome in Guillain-Barré syndrome (GBS) is axonal degeneration. Pathways leading to primary axonal injury in the motor axonal variant are well established, whereas mechanisms of secondary axonal injury in acute inflammatory demyelinating polyneuropathy (AIDP) are unknown. We recently developed an autoantibody-and complement-mediated model of murine AIDP, in which prominent injury to glial membranes at the node of Ranvier results in severe disruption to paranodal components. Acutely, axonal integrity was maintained, but over time secondary axonal degeneration occurred. Herein, we describe the differential mechanisms underlying acute glial membrane injury and secondary axonal injury in this model. Ex vivo nerve-muscle explants were injured for either acute or extended periods with an autoantibody-and complement-mediated injury to glial paranodal membranes. This model was used to test several possible mechanisms of axon degeneration including calpain activation, and to monitor live axonal calcium signalling. Glial calpains induced acute disruption of paranodal membrane proteins in the absence of discernible axonal injury. Over time, we observed progressive axonal degeneration which was markedly attenuated by axon-specific calpain inhibition. Injury was unaffected by all other tested methods of protection. Trans-axolemmal diffusion of fluorescent proteins and live calcium imaging studies indirectly demonstrated the presence of nanoruptures in the axon membrane. This study outlines one mechanism by which secondary axonal degeneration arises in the AIDP variant of GBS where acute paranodal loop injury is prominent. The data also support the development of calpain inhibitors to attenuate both primary and secondary axonal degeneration in GBS.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Campbell, Ms Clare and McGonigal, Dr Rhona and Cunningham, Dr Madeleine and Barrie, Mrs Jennifer and Willison, Professor Hugh and Yao, Dr Denggao |
| Authors: | Cunningham, M. E., McGonigal, R., Barrie, J. A., Campbell, C. I., Yao, D., and Willison, H. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
| Journal Name: | Journal of the Peripheral Nervous System |
| Publisher: | Wiley |
| ISSN: | 1085-9489 |
| ISSN (Online): | 1529-8027 |
| Published Online: | 29 January 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Journal of the Peripheral Nervous System 28(1):17-31 |
| Publisher Policy: | Reproduced under a Creative Commons License |
| Data DOI: | 10.5525/gla.researchdata.1361 |
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