Fabris, Federico;
Megighian, Aram;
Rossetto, Ornella;
Simonato, Morena;
Schiavo, Giampietro;
Pirazzini, Marco;
Montecucco, Cesare;
(2024)
Local Tetanus Begins with a Vesicle-Associated Membrane Protein Cleavage–Associated Neuromuscular Junction Paralysis around the Site of Tetanus Neurotoxin Release.
American Journal of Pathology
10.1016/j.ajpath.2024.05.009.
(In press).
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Abstract
Local tetanus develops when limited amounts of tetanus neurotoxin (TeNT) are released by Clostridium tetani generated from spores inside a necrotic wound. Within days, a spastic paralysis restricted to the muscles of the affected anatomical area develops. This paralysis follows the retrograde transport of TeNT inside the axons of spinal cord motoneurons and its uptake by inhibitory interneurons with cleavage of VAMP, a synaptic vesicle protein required for neurotransmitter release. Consequently, incontrollable excitation of motoneurons causes contractures of innervated muscles and to local spastic paralysis. Here, the initial events occurring close to the site of TeNT release were investigated in a mouse model of local tetanus. A peripheral flaccid paralysis was found to occur, before or overlapping, the spastic one. At variance from the confined TeNT proteolytic activity at the periphery, central VAMP cleavage can be detected within inhibitory interneurons controlling motor neuron efferents innervating muscle groups distant from the site of TeNT release. These results indicate that TeNT does have a peripheral activity in tetanus and explains why the spastic paralysis observed in local tetanus, although confined to single limbs, generally affects multiple muscles. The initial TeNT neuroparalytic activity can be detected by measuring the compound muscle action potential providing a very early diagnosis and therapy thus preventing the ensuing life-threatening generalized tetanus.
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