Complex gangliosides at the neuromuscular junction are membrane receptors for autoantibodies and botulinum neurotoxin but redundant for normal synaptic function.
One specialization of vertebrate presynaptic neuronal membranes is their multifold enrichment in complex gangliosides, suggesting that these sialoglycolipids may play a major functional role in synaptic transmission. We tested this hypothesis directly by studying neuromuscular synapses of mice lacking complex gangliosides attributable to deletion of the gene coding for beta1,4 GalNAc-transferase (GM2/GD2 synthase), which catalyzes an early step in ganglioside synthesis. Our studies show that complex gangliosides are surprisingly redundant for regulated neurotransmitter release under normal physiological conditions. In contrast, we show that they are membrane receptors for both the paralytic botulinum neurotoxin type-A and human neuropathy-associated anti-ganglioside autoantibodies that arise through molecular mimicry with microbial structures. These data prove the critical importance of complex gangliosides in mediating pathophysiological events at the neuromuscular synapse.
Bullens
Roland W M
RW
Department of Neurology, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands.
O'Hanlon
Graham M
GM
Wagner
Eric
E
Molenaar
Peter C
PC
Furukawa
Keiko
K
Furukawa
Koichi
K
Plomp
Jaap J
JJ
Willison
Hugh J
HJ
D000109:Acetylcholine / Q000096:biosynthesis; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001323:Autoantibodies / Q000097:blood* / Q000494:pharmacology; D019274:Botulinum Toxins, Type A / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004558:Electric Stimulation; D004594:Electrophysiology; D005732:Gangliosides / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008839:Microelectrodes; D019846:Miller Fisher Syndrome / Q000097:blood / Q000276:immunology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D017350:N-Acetylgalactosaminyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D005732:Gangliosides; D011956:Receptors, Cell Surface; C039129:GQ1b ganglioside; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase; D019274:Botulinum Toxins, Type A; D000109:Acetylcholine; D002118:Calcium