Cytotoxicity of botulinum neurotoxins revealsa direct role of syntaxin 1 and SNAP-25in neuron survival

摘要

Botulinum neurotoxins (BoNT/A–G) act by blocking synaptic vesicle exocytosis. WhetherBoNTs disrupt additional neuronal functions has not been addressed. Here we report thatcleavage of syntaxin 1 by BoNT/C, and cleavage of SNAP-25 by BoNT/E both inducedegeneration of neurons. Furthermore, although SNAP-25 cleaved by BoNT/A still supportsneuron survival, it has reduced capacity to tolerate additional mutations. We demonstratethat syntaxin 1 and SNAP-25 cooperate as SNARE proteins to support neuron survival.Exogenous expression of other homologous SNARE proteins, syntaxin 2/3/4 and SNAP-23,which are resistant to BoNT/C and E in neurons, can substitute syntaxin 1/SNAP-25 andprevent toxin-induced neuron death. Finally, we find that neuronal death is due to blockage ofplasma membrane recycling processes that utilize syntaxin 1/SNAP-25, independent ofsynaptic vesicle exocytosis. These findings establish neuronal cytotoxicity for BoNTs andreveal syntaxin 1/SNAP-25 as the ubiquitous and essential SNARE proteins mediating multiplefusion events on neuronal plasma membranes.