Absorption and transport of botulinum neurotoxins

Abstract

Botulinum neurotoxin (BoNT) is a potent toxin, which blocks the neurotransmitter release at neuromuscular junctions. BoNT can be acquired from the digestive tract (food-borne botulism, Clostridium botulinum intestinal colonization), respiratory tract (inhalational botulism), or wound (wound botulism). BoNT associates to nontoxic proteins (ANTPs), which have a main role in toxin protection against acidic pH and proteases, especially in the gastrointestinal tract. BoNT, which enters through the digestive or respiratory tract, has to first cross the epithelial barrier. This is achieved by a receptor-mediated transcytosis, which delivers the whole and active toxin at the basolateral side of epithelial cells. ANTPs containing hemagglutinins (HAs) may have an additional role in altering the intercellular junctions and facilitating 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 motor neuron endings, where the toxin uses an endocytic pathway permitting the release of the light (L)- chain into the cytosol and its subsequent proteolytic activity towards the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins involved in the neurotransmitter exocytosis.