Nidogens are new therapeutic targets for the prevention of tetanus

Tetanus neurotoxin (TeNT) is one of the most poisonous substances on Earth and a major cause of neonatal death in non-vaccinated areas (1). TeNT targets the neuromuscular junction (NMJ) with high affinity, yet the nature of the TeNT receptor complex at the NMJ remains unknown (2). Here we show that nidogens (also known as entactins (3)) are highly enriched at the basement membrane of the NMJ and are essential for TeNT binding to motor neurons, where TeNT enters the central nervous system to exert its toxic effects. Inhibition of the TeNT-nidogen interaction using small nidogen-derived peptides or genetic ablation of nidogen-2 protects mice from TeNT-induced spastic paralysis. Our report is the first to demonstrate the direct involvement of a protein receptor for TeNT at the NMJ, paving the way for the development of novel therapeutics for the prevention of tetanus targeting this novel protein-protein interaction.