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 8

Extended in vivo injury selectively targeting glial membrane results in secondary axonal degeneration.

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Extended in vivo injury selectively targeting glial membrane results in ...
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). The experiment was terminated 24 hours after NHS delivery. The site of expected nodal protein immunostaining is indicated by arrowheads. (A) At this time point there was loss of neurofilament H staining (NFH, orange) at the motor nerve terminal (MNT, asterisk) and the staining intensity was significantly reduced at the first distal node of Ranvier (NoR). (B) Normal ankyrin B (AnkB), NF155, NF186, and Caspr1 (magenta) immunostaining was assessed at distal paranodes after injury compared to control. (C) There was a further reduction in distal NoRs with normal voltage-gated sodium (Nav) channel staining (magenta) in injured Glial mice compared with control at this extended time point. (D) Additionally, the Nav channel–tethering protein AnkG was notably absent. Scale bar: 5 μm. Results are represented as the mean ± SEM. n = 3/genotype/treatment: 5–15 NoRs/mouse (median = 11, NFH intensity); 4–25 NoRs/mouse (median = 18, panNFasc); 9–23 NoRs/mouse (median = 12, Nav); and 10–28 NoRs/mouse (median = 18, AnkG) were analyzed. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed Student’s t test (A and B) or 2-way ANOVA with Tukey’s post hoc test (C).