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The Journal of Neuroscience, August 15, 2002, 22(16):6876-6884

Complex Gangliosides at the Neuromuscular Junction Are Membrane Receptors for Autoantibodies and Botulinum Neurotoxin But Redundant for Normal Synaptic Function

Roland W. M. Bullens^{1, 2}, Graham M. O'Hanlon³, Eric Wagner³, Peter C. Molenaar², Keiko Furukawa⁴, Koichi Furukawa⁴, Jaap J. Plomp^{1, 2}, and Hugh J. Willison³

Departments of ¹ Neurology and ² Physiology, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands, ³ University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, G51 4TF, Scotland, and ⁴ Department of Biochemistry II, Nagoya University School of Medicine, Showa-ku, Nagoya 466-0065, Japan

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 1,4 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.

Key words: complex gangliosides; neuromuscular junction; synaptic transmission; botulinum neurotoxin; anti-ganglioside antibodies; Miller Fisher syndrome; 1,4 GalNAc-transferase

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22166876-09$05.00/0

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