Abstract
Tetanus neurotoxin (TeNT) is a protein exotoxin produced by Clostridium tetani that causes the deadly spastic neuroparalysis of tetanus. It consists of a metalloprotease light chain and of a heavy chain linked via a disulphide bond. TeNT binds to the neuromuscular junction (NMJ) and it is retro-axonally transported into vesicular compartments to the spinal cord, where it is released and taken up by inhibitory interneuron. Therein, the catalytic subunit is translocated into the cytoplasm where it cleaves its target protein VAMP-1/2 with consequent blockage of the release of inhibitory neurotransmitters. Vaccination with formaldehyde inactivated TeNT prevents the disease, but tetanus is still present in countries where vaccination coverage is partial. Here, we show that small molecule inhibitors interfering with TeNT trafficking or with the reduction of the interchain disulphide bond block the activity of the toxin in neuronal cultures and attenuate tetanus symptoms in vivo. These findings are relevant for the development of therapeutics against tetanus based on the inhibition of toxin molecules that are being retro-transported to or are already within the spinal cord and are, thus, not accessible to anti-TeNT immunoglobulins.
Highlights
Tetanus neurotoxin (TeNT) is produced by Clostridium tetani and together with botulinum neurotoxins (BoNTs) forms the large, and still growing, family of ClostridialNeurotoxins (CNTs) [1,2,3]
Following the demonstration that the cytosolic reduction of the interchain disulphide bond of CNTs is essential to enable their metalloprotease activity [23,24] and the recent finding that TrxR–Trx inhibitors prevent the toxicity of all BoNT serotypes [45], we investigated whether TrxR–Trx inhibitors prevent TeNT intoxication in vitro
CNTs toxicity is visualization of cleavage of their substrates using cerebellar granular neurons (CGNs) which are very sensitive to TeNT [48]
Summary
Tetanus neurotoxin (TeNT) is produced by Clostridium tetani and together with botulinum neurotoxins (BoNTs) forms the large, and still growing, family of ClostridialNeurotoxins (CNTs) [1,2,3]. The CNTs are the etiological agents of botulism (BoNTs) and tetanus (TeNT), two deadly neuroparalytic syndromes affecting vertebrates characterized by a flaccid and a spastic paralysis, respectively. They are the most poisonous substances known to mammalians with lethal doses in the low ng/kg range [4]. The opposite symptoms of flaccid and spastic paralysis solely depend on BoNTs and TeNT targeting different neurons. This is dictated by the carboxyl-terminal fragment of H (HC) [6,7] that binds the presynaptic membrane at the neuromuscular junction (NMJ)
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