Anti-GM1 Antibodies Cause Complement-Mediated Disruption of Sodium Channel Clusters in Peripheral Motor Nerve Fibers

TLDR

Voltage‑gated Na⁺ channels cluster at nodes of Ranvier to enable rapid conduction, and autoantibodies to ganglioside GM1 are thought to disrupt these channels, contributing to Guillain‑Barré syndrome’s acute limb weakness. The study aimed to test this hypothesis by examining the molecular organization of nodes in a ganglioside‑immunized disease model. Researchers assessed node architecture in the model, focusing on the distribution of Na⁺ channel clusters, paranodal junctions, cytoskeletal elements, and Schwann cell microvilli. Acute IgG and complement deposition at nodes caused loss of Na⁺ channel clusters and associated structures, while recovery saw decreased complement and channel redistribution, demonstrating that complement‑mediated disruption of axon–Schwann cell interactions underlies node disruption in acute motor axonal neuropathy.

Abstract

Voltage-gated Na + (Na v ) channels are highly concentrated at nodes of Ranvier in myelinated axons and facilitate rapid action potential conduction. Autoantibodies to gangliosides such as GM1 have been proposed to disrupt nodal Nav channels and lead to Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness. To test this hypothesis, we examined the molecular organization of nodes in a disease model caused by immunization with gangliosides. At the acute phase with progressing limb weakness, Na v channel clusters were disrupted or disappeared at abnormally lengthened nodes concomitant with deposition of IgG and complement products. Paranodal axoglial junctions, the nodal cytoskeleton, and Schwann cell microvilli, all of which stabilize Na v channel clusters, were also disrupted. The nodal molecules disappeared in lesions with complement deposition but no localization of macrophages. During recovery, complement deposition at nodes decreased, and Na v channels redistributed on both sides of affected nodes. These results suggest that Na v channel alterations occur as a consequence of complement-mediated disruption of interactions between axons and Schwann cells. Our findings support the idea that acute motor axonal neuropathy is a disease that specifically disrupts the nodes of Ranvier.