Clostridial neurotoxins: from the cellular and molecular mode of action to their therapeutic use
Résumé
Botulinum (BoNT) and tetanus (TeNT) neurotoxins are potent toxins responsible for flaccid and spastic paralysis, respectively. BoNTs are divided into types and subtypes according to their immunological properties and amino acid sequence variations, whereas only one type of TeNT has been characterized. BoNTs associate with nontoxic proteins to form large complexes that are resistant to acidic pH and protease degradation, unlike TeNT, which is produced as a unique protein. BoNTs and TeNT enter target neuronal cells by interacting with specific cell surface receptors. BoNTs proteolytically cleave soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (SNAP-25, VAMP, or syntaxin) mainly at the cholinergic neuromuscular junctions impairing the evoked release of acetylcholine, whereas TeNT inhibits the neuroexocytosis in central inhibitory interneurons by cleavage of VAMP. BoNT-mediated muscle paralysis induces neuronal sprouting, which after various time periods, leads to a recovery of neurotransmission. BoNT/A, which has a long duration of activity, is used in numerous medical applications.