Botulinum neurotoxins: from the gut to the nervous system

Abstract

Botulinum neurotoxins (BoNTs) are potent toxins, which block the neurotransmitter release at neuromuscular junctions and are responsible for a severe disease, the botulism. In the natural disease, BoNTs are the most frequently acquired by the oral route. BoNT associates to non-toxic proteins (ANTPs), which have a main role in toxin protection against acidic pH and proteases, especially in the gastrointestinal tract. BoNTs which transit through the digestive tract, have first to cross the epithelial barrier. BoNTs are able to undergo a receptor-mediated transcytosis, which delivers the whole and active toxin at the basolateral side of epithelial cells. ANTPs containing hemagglutinins have an additional role in altering the intercellular junctions and facilitating a toxin passage through the paracellular way. Then, BoNT disseminates locally and at distance via the blood/lymph circulation and possibly via a retrograde axonal transport to the target motoneuron endings, where the toxin uses an endocytic pathway permitting the release of the light chain into the cytosol and its subsequent proteolytic activity towards the SNARE proteins involved in the neurotransmitter exocytosis.