An animal model of Miller Fisher syndrome: Mitochondrial hydrogen peroxide is produced by the autoimmune attack of nerve terminals and activates Schwann cells

Abstract

The neuromuscular junction is a tripartite synapse composed of the presynaptic nerve terminal, the muscle and perisynaptic Schwann cells. Its functionality is essential for the execution of body movements and is compromised in a number of disorders, including Miller Fisher syndrome, a variant of Guillain-Barré syndrome: this autoimmune peripheral neuropathy is triggered by autoantibodies specific for the polysialogangliosides GQ1b and GT1a present in motor axon terminals, including those innervating ocular muscles, and in sensory neurons. Their binding to the presynaptic membrane activates the complement cascade, leading to a nerve degeneration that resembles that caused by some animal presynaptic neurotoxins. Here we have studied the intra- and inter-cellular signaling triggered by the binding and complement activation of a mouse monoclonal anti-GQ1b/GT1a antibody to primary cultures of spinal cord motor neurons and cerebellar granular neurons. We found that a membrane attack complex is rapidly assembled following antibody binding, leading to calcium accumulation, which affects mitochondrial functionality. Consequently, using fluorescent probes specific for mitochondrial hydrogen peroxide, we found that this reactive oxygen species is rapidly produced by mitochondria of damaged neurons, and that it triggers the activation of the MAP kinase pathway in Schwann cells. These results throw light on the molecular and cellular pathogenesis of Miller Fisher syndrome, and may well be relevant to other pathologies of the motor axon terminals, including some subtypes of the Guillain Barré syndrome.

Correlations between microRNA-146a and immunoglobulin and inflammatory factors in Guillain–Barré syndrome

“…Loss of glial protein clusters at the nodes reduces the anchoring ability between myelin and axons and thus leads to demyelination of the nerve roots. [10][11][12][13] Yang et al 14 found that levels of IgG (but not of IgA and IgM) differed in the peripheral blood of patients with GBS and healthy individuals, similar to our results. This indicates that IgG plays an important role in the pathogenesis of GBS.…”

Fluorogenic Probe Using a Mislow–Evans Rearrangement for Real‐Time Imaging of Hydrogen Peroxide

“…Generally, chemical probes for H 2 O 2 detect endogenously produced H 2 O 2 later times (ca. 30 min) . In the zebrafish tail wounding model, we observed the rapid generation of H 2 O 2 near the wound site in real time using selenide 1 , recapitulating the results using a protein‐based probe …”

“…When these probes were applied in biological systems, it took ca. 30 min to produce fluorescence signals …”

Schwann cells are activated by ATP released from neurons in an in vitro cellular model of Miller Fisher syndrome

“…The ERK1/2 pathway is also activated in SCs co-cultured with neurons upon exposure to FS3+NHS (Rodella et al, 2016). The transcriptional factor CREB, which is known to participate in many cellular processes and in neuron-glia communication, is among the targets of both ERK1/2 and cAMP pathways (Tabernero et al, 1998).…”

“…We have recently shown that the crucial pathogenic steps of MFS can be reproduced in vitro by exposing primary neurons to the combination of the monoclonal anti-GQ1b/GT1a IgG antibody (FS3) plus NHS as a source of complement (Rodella et al, 2016). FS3 was obtained by inoculating mice with a lysate of heat-killed Campylobacter jejuni , the infectious agent most frequently associated with MFS (Koga et al, 2005).…”