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 2

Distal motor nerve integrity following selective targeting and acute injury of neural membranes ex vivo.

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Distal motor nerve integrity following selective targeting and acute inj...
Triangularis sterni nerve–muscle preparations from WT, Neuronal, and Glial mice were treated ex vivo with anti-GM1 Ab and a source of complement (injury, Inj) or anti-GM1 Ab alone (control, Con). (A) Loss of axonal integrity due to injury at the motor nerve terminal (MNT, identified by α-bungarotoxin, BTx, orange, asterisk) and node of Ranvier (NoR, orange, arrowheads) was monitored by presence of neurofilament H immunostaining (NFH, magenta). Membrane attack complex (MAC) complement pore deposition (green) was present in all injured preparations compared with control. (B) Ethidium homodimer–positive (EthD-2–positive, orange) cells overlying MNT (magenta, asterisk) were compared among treatment groups. Representative images show the presence of complement deposition (green) in all injured tissue. (C and D) The sites where ankyrin B (AnkB) or AnkG immunostaining should be located are indicated by arrowheads. The presence of normal (black bars, statistical comparisons indicated with asterisks) or abnormal (gray bars) AnkB and AnkG immunostaining was compared to associated controls for each genotype. A lengthened gap between AnkB domains is shown in a representative image from injured Neuronal tissue. Weakened, uneven AnkG staining in injured Glial tissue is shown in the representative image. Scale bars: 20 μm (A), 50 μm (B), and 5 μm (C and D). Results are represented as the mean ± SEM. n = 3/genotype/treatment: 10–46 NoRs/mouse (median = 21, NFH); 11–29 neuromuscular junctions (NMJs)/mouse (median = 18, EthD-2); 10–26 NoRs/mouse (median = 23, AnkG); and 12–31 NoRs/mouse (median = 21, AnkB) were analyzed. *P < 0.05; ***P < 0.001; ###P < 0.001 (for abnormal AnkB and AnkG immunostaining in C) compared with control by 2-way ANOVA with Tukey’s post hoc test.