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 4

Distal motor nerve axonal integrity remains intact following selective glial membrane targeting in vivo.

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Distal motor nerve axonal integrity remains intact following selective g...
WT, 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, Inj) or NHS only (control, Con). Respiratory function was monitored and diaphragm distal nerves assessed by immunoanalysis 5 hours after NHS delivery. (A) Injured Neuronal mice displayed the most severe respiratory phenotype: a pinched, wasp-like abdomen (arrowheads) and significantly reduced tidal volume (TV) measured using whole-body plethysmography (EMMS). Injured Glial mice also had significantly reduced TV compared with baseline. Representative respiratory flow charts for each treatment group show reduced TV and an increase in respiratory rate. Serum analysis indicates that circulating anti-GM1 Ab could be detected in Neuronal and Glial but not WT mice. Results are represented as the mean ± SEM, n = 4/genotype/treatment. (B) Complement deposition and axonal integrity (neurofilament H [NFH] occupancy) were compared at the diaphragm motor nerve terminals (MNTs) and along distal nerves. Representative images illustrate complement deposits (green) overlying the MNT, identified by bungarotoxin (BTx, orange), in injured Neuronal mice, and on the distal nerve in injured WT and Glial mice. Scale bar: 10 μm. Results are represented as the mean ± SEM. n = 4/genotype/treatment: 68–133 MNTs/mouse (median = 103) and 7–30 NoRs/mouse (median = 15) were analyzed. *P < 0.05, **P < 0.01, ***P < 0.001 by repeated measures 2-way ANOVA with Bonferroni post-hoc tests (A) or 2-way ANOVA with Tukey post-hoc tests (B).