An animal model of Miller Fisher syndrome: Mitochondrial hydrogen peroxide is produced by the autoimmune attack of nerve terminals and activates Schwann cells.
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.
Department of Biomedical Sciences, University of Padua, Padua, Italy.
Umberto
U
Rodella
Department of Biomedical Sciences, University of Padua, Padua, Italy.
Michele
M
Scorzeto
Department of Biomedical Sciences, University of Padua, Padua, Italy.
Elisa
E
Duregotti
Department of Biomedical Sciences, University of Padua, Padua, Italy.
Samuele
S
Negro
Department of Chemistry, The University of Chicago, Chicago, IL, USA.
Bryan C
BC
Dickinson
Department of Chemistry and Molecular and Cell Biology, University of California, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
Christopher J
CJ
Chang
Department of Neurology, Mishima Hospital, Niigata, Japan.
Nobuhiro
N
Yuki
Department of Biomedical Sciences, University of Padua, Padua, Italy. Electronic address: rigonimic@gmail.com.
Michela
M
Rigoni
Department of Biomedical Sciences, University of Padua, Padua, Italy; CNR Institute of Neuroscience, Padua, Italy. Electronic address: cesare.montecucco@gmail.com.
Cesare
C
Montecucco
D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D005732:Gangliosides / Q000276:immunology / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007074:Immunoglobulin G / Q000494:pharmacology; D008297:Male; D051379:Mice; D019846:Miller Fisher Syndrome / Q000150:complications* / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction / Q000187:drug effects; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
D005732:Gangliosides; D007074:Immunoglobulin G; D050494:Vesicular Acetylcholine Transport Proteins; C084318:GT1aalpha ganglioside; C039129:GQ1b ganglioside; D006861:Hydrogen Peroxide
ERK1/2; Hydrogen peroxide; Miller Fisher syndrome; Neuromuscular junction; Schwann cells