Neurotrophic effects of Botulinum neurotoxin type A in hippocampal neurons involve activation of Rac1 by the non-catalytic heavy chain (HCC/A)

Botulinum neurotoxins (BoNTs) are extremely potent naturally occurring poisons that act by silencing neurotransmission. Intriguingly, in addition to preventing presynaptic vesicle fusion, BoNT serotype A (BoNT/A) can also promote axonal regeneration in preclinical models. Here we report that the non-toxic C-terminal region of the receptor-binding domain of heavy chain BoNT/A (HCC/A) activates the small GTPase Rac1 and ERK pathway to potentiate axonal outgrowth, dendritic protrusion formation and synaptic vesicle release in hippocampal neurons. These data are consistent with HCC/A exerting neurotrophic properties, at least in part, independent of any BoNT catalytic activity or toxic effect. •The non-catalytic, non-toxic C-terminal region of the heavy chain of BoNT/A (HCC/A) activates Rac1 and ERK.•HCC/A promotes axonal outgrowth and dendritic filopodia.•HCC/A enhances synaptic vesicle release.