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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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 3

Differential disruption to the node of Ranvier when neuronal and glial membranes are injured selectively ex vivo.

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Differential disruption to the node of Ranvier when neuronal and glial m...
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). Disruption to nodal protein (magenta) organization at the node of Ranvier (NoR) due to injury was assessed; the site of expected staining is indicated by arrowheads for each marker. Representative images demonstrate normal nodal protein localization in all control tissue and absent or abnormal staining in injury groups, which coincides with nodal complement deposition (A and C, green). (A) A pan-neurofascin (Nfasc) Ab was used to assess paranodal NF155 (closed arrowheads) and nodal NF186 (open arrowhead). (B) SC microvilli marker gliomedin (Gldn) immunostaining at NoRs was assessed compared to controls. Asterisks indicate motor nerve terminals. (C) Changes to normal (black bars) Nav1.6 labeling were observed in injured tissue from all genotypes compared with associated controls. Diamond defines statistical comparisons of absent immunostaining (white bars). (D) Perineural recordings from distal motor nerves were performed on tissue from Neuronal and Glial mice treated with anti-GM1 Ab only, a source of complement (normal human serum, NHS) only, or a combination of Ab and NHS (injured). Representative recordings from 1 mouse per treatment demonstrate that normal Na+ and K+ waveforms were lost when the tissue was injured. Scale bar: 5 μm. Results are represented as the mean ± SEM. n = 3/genotype/treatment: 13–36 NoRs/mouse (median = 24, pNFasc); 15–33 NoRs/mouse (median = 19, gliomedin); and 11–30 NoRs/mouse (median = 23, Nav1.6) were analyzed. *P < 0.05, **P < 0.01, ***P < 0.001 (for comparisons between normal immunostaining); ###P < 0.001 (for abnormal NF155 immunostaining in Neuronal injury group compared to WT or Glial imjury in A) compared with control by 2-way ANOVA with Tukey’s post hoc test.