Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model
Rhona McGonigal, … , Edward G. Rowan, Hugh J. Willison
Rhona McGonigal, … , Edward G. Rowan, Hugh J. Willison
Published June 7, 2022
Citation Information: J Clin Invest. 2022;132(14):e158524. https://doi.org/10.1172/JCI158524.
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Research Article Autoimmunity Neuroscience

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

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.

Authors

Rhona McGonigal, Clare I. Campbell, Jennifer A. Barrie, Denggao Yao, Madeleine E. Cunningham, Colin L. Crawford, Simon Rinaldi, Edward G. Rowan, Hugh J. Willison

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Figure 6

Ultrastructural evaluation of diaphragms from in vivo injury models.

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Ultrastructural evaluation of diaphragms from in vivo injury models. Neu...
Neuronal and Glial mice were dosed i.p. with 50 mg/kg anti-GM1 Ab followed 16 hours later with 30 μL/g normal human serum (NHS) (injury) or NHS only (control). (A) A normal paranode from Glial control tissue. N.B. This image is also representative of the Neuronal control NoR (not shown). (B) Higher magnification of boxed region from A shows tight junctions (large arrowhead) between the paranodal loops, and transverse bands (TBs, small arrowheads) at the axo-glial junction between the axon and paranodal loops. (C) Injured Glial NoRs show severely disrupted paranodal loop organization compared with control. (D) Magnification of boxed area from C, shows TBs are present between the paranodal loops and axon at the juxtaparanodal-proximal paranode (above black line); however, they are absent at the node-proximal border (above white line, right of asterisk). (E) Injured Neuronal NoRs show no architectural disruption. (F) Neuronal control motor nerve terminal (MNT) displays normal architecture and contains synaptic vesicles (black arrows). (G) Disturbance to the injured Neuronal MNT includes an absence of neurofilament, synaptic vesicles, and the formation of dense or vacuolated mitochondria (white arrows). Results are representative of analysis from 8–10 NoRs per mouse (n = 3/genotype/treatment).