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 1

Anti–GM1 ganglioside antibody binding in transgenic mice with selective neuronal or glial complex ganglioside expression.

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Anti–GM1 ganglioside antibody binding in transgenic mice with selective ...
(A) Constructs used to direct GalNAc-T expression in neurons (human Thy1.2 promoter) or glia (mouse Plp promoter) of GalNAc-T–/–-Tg(neuronal) (Neuronal) and GalNAc-T–/–-Tg(glial) (Glial) mice, respectively. Ganglioside biosynthesis pathway indicates the reexpression of complex ganglioside expression (gray box) following construct insertion on a GalNAc-T–/– background (20). (B) Using a single anti-GM1 antibody (Ab, green), differential binding was observed at the distal motor nerves from triangularis sterni nerve–muscle preparations among genotypes. Open arrowheads indicate internodal Schwann cell (SC) abaxonal membrane anti-GM1 Ab deposition on WT and Glial nerves (absent along Neuronal nerves). Gliomedin (Gldn) immunostaining identifies the nodal gap. Boxed areas are enlarged underneath and represent differential anti-GM1 Ab binding at nodes of Ranvier (NoRs) among genotypes in relation to gliomedin (closed arrowheads). Dashed lines delineate the border of the axonal membrane determined by cytoplasmic CFP–positive axons. Scale bars: 10 μm (top panels) and 5 μm (lower panels). Asterisks indicate motor nerve terminals. (C) Caspr1 immunostaining (magenta) indicates the paranodes. Dashed lines delineate the border of the axonal membrane and arrowheads indicate anti-GM1 Ab binding beyond this membrane, suggesting binding on the glial membranes of the SC microvilli (open arrowheads) or paranodal loops (closed arrowheads) at WT and Glial NoRs. Scale bar: 2 μm.