Bercsenyi, K; (2015) Nidogens are therapeutic targets for the prevention of tetanus. Doctoral thesis , UCL (University College London).

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Abstract

Tetanus neurotoxin (TeNT) is among the most poisonous substances on Earth and a major cause of neonatal death in non-vaccinated areas. There are approximately 300,000 cases reported worldwide each year, and the mortality rate is between 10-20%. In this work, I identified an extracellular matrix protein receptor for TeNT at the neuromuscular junction (NMJ) and developed a peptide inhibitor, which prevents tetanic paralysis in vivo in mice. TeNT binds to the NMJ with an extremely high affinity, yet the nature of its receptor complex was poorly understood. I showed that the presence of nidogens (also known as entactins) at the NMJ is the main determinant for TeNT binding. Nidogens are extracellular matrix (ECM) proteins, which are taken up into the endosomal carriers containing tetanus toxin binding fragment (HCT) in motor neurons. Inhibition of the HCT-nidogen interaction using a peptide originating from nidogen-1 abolishes HCT binding on these cells. TeNT causes slowly progressing local tetanus when it is injected intramuscularly into the triceps surae muscle in a low dose. When preincubated with the peptide originating from nidogen-1, TeNT injection does not alter the coordination of mice and the muscle force remains largely unchanged. Genetic ablation of nidogens prevented the binding of TeNT to neurons and the intact NMJ and protected mice from TeNT induced spastic paralysis. In my thesis I demonstrated for the first time, that an ECM protein accumulates and presents a neurotropic pathogen to the presynapse. This study follows recent studies showing that growth factors trigger downstream signalling more efficiently if they bind to certain ECM components – a new and rising concept in neuroscience.

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