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Science. 2014 Nov 28;346(6213):1118-23. doi: 10.1126/science.1258138.

Tetanus toxin entry. Nidogens are therapeutic targets for the prevention of tetanus.

Author information

1
Molecular Neuropathobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, University College London, London WC1N 3BG, UK.
2
Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, University College London, London WC1N 3BG, UK.
3
Department of Biomedical Sciences, University of Padua, Viale G. Colombo 3, 35131 Padova, Italy.
4
Molecular Neuropathobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
5
Department of Dermatology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
6
Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, University College London, London WC1N 3BG, UK. giampietro.schiavo@ucl.ac.uk.

Abstract

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.

PMID:
25430769
DOI:
10.1126/science.1258138
[Indexed for MEDLINE]
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