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 5

Disruption of paranodal proteins following glial membrane targeting in vivo.

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Disruption of paranodal proteins following glial membrane targeting in v...
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). The site of expected nodal protein immunostaining is indicated by arrowheads. (A) The presence of normal ankyrin B (AnkB) immunostaining at the distal paranode (black bars) was significantly reduced in injured Glial mice compared with all treatment groups in the presence of complement (green). (B) A pan-neurofascin (Nfasc) Ab was used to assess glial NF155 and axonal NF186 (magenta). Representative images show loss of NF155 staining at paranodal regions, indicated by dashed lines, and the preservation of NF186 when NoRs are decorated with anti-GM1 Ab (green) in Glial mice. (C) Normal Caspr1 (orange) immunostaining at the distal paranodes was significantly reduced in injured Glial mice compared with all other treatment groups. (D) There was a reduction in distal NoRs with normal Nav channel (orange) staining in injured Neuronal mice. Scale bar: 5 μm. Results are represented as the mean ± SEM. n = 4/genotype/treatment: 5–46 NoRs/mouse (median = 21, AnkB); 7–53 NoRs/mouse (median = 25, NFasc); 5–15 NoRs/mouse (median = 11, Caspr1); and 11–27 NoRs/mouse (median = 16, Nav) were analyzed. *P < 0.05, **P < 0.01, ***P < 0.001 for comparisons with the other treatment groups (A, C, and D) or compared with control (B) by 2-way ANOVA with Tukey’s post hoc test.