Nidogens are therapeutic targets for the prevention of tetanus

Science  28 Nov 2014:
Vol. 346, Issue 6213, pp. 1118-1123
DOI: 10.1126/science.1258138

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Tetanus neurotoxin (TeNT) is among the most poisonous substances on Earth and a major cause of neonatal death in nonvaccinated areas. TeNT targets the neuromuscular junction (NMJ) with high affinity, yet the nature of the TeNT receptor complex remains unknown. Here, we show that the presence of nidogens (also known as entactins) at the NMJ is the main determinant for TeNT binding. Inhibition of the TeNT-nidogen interaction by using small nidogen-derived peptides or genetic ablation of nidogens prevented the binding of TeNT to neurons and protected mice from TeNT-induced spastic paralysis. Our findings demonstrate the direct involvement of an extracellular matrix protein as a receptor for TeNT at the NMJ, paving the way for the development of therapeutics for the prevention of tetanus by targeting this protein-protein interaction.

A potential peptide to prevent tetanus?

Tetanus (TeNT) and botulinum (BoNT) neurotoxins represent a family of powerful bacterial protein toxins that cause tetanus and botulism in humans and animals. The molecular mechanisms responsible for the entry and axonal retrograde transport of these toxins have been the subject of intense research. However, tetanus and botulism remain incurable, at least in part because of their high-affinity binding to synapses. Although the receptors for BoNT have recently been characterized at the molecular level, no protein receptor for TeNT at the neuromuscular junction has been identified. Bercsenyi et al. now suggest that TeNT exploits nidogen-1 and -2 for its binding to motor neurons. This binding is required for TeNT's internalization and axonal retrograde transport. Nidogens are extracellular matrix proteins that engage in multiple protein-protein interactions essential for the integrity of several tissues, including the nervous system. Interfering with the interaction between nidogens and TeNT by administering short nidogen-derived peptides blocked toxin binding to the neuromuscular junction and protected mice from tetanus.

Science, this issue p. 1118

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