Response from Facchiano, Innamorati and Luini

Coffield et al. discuss three hypotheses that have been proposed recently for the mode of action of the clostridial neurotoxins. They conclude that the mechanism of toxin action suggested by Schiavo et al. ‘v2, that is, by proteolytic cleavage of essential synaptic proteins, is supported by substantial evidence and explains toxin-induced neuroparalysis elegantly. By contrast, they suggest that there are reasons to be cautious about the other two hypotheses, which implicate the enzymes transglutaminase (TGase)“,4 and phospholipase A, (PLA,)’ in the neuroparalytic effects of the toxins. We could not agree more about the power and elegance of the proteolytic mechanism first demonstrated by Cesare Montecucco and colleagues, and later confirmed by Link et aL6. Indeed, we believe that their idea that the short-term effects of clostridial toxins depend on the proteolysis of proteins essential for exocytosis’ is sound, and will be rapidly and universally accepted.