Peng, LishengLiu, HuishengRuan, HongyuTepp, William H.Stoothoff, William H.Brown, Robert H.Johnson, Eric A.Dong, MinYao, Wei-DongZhang, Su-Chun2014-07-072014Peng, Lisheng, Huisheng Liu, Hongyu Ruan, William H. Tepp, William H. Stoothoff, Robert H. Brown, Eric A. Johnson, Wei-Dong Yao, Su-Chun Zhang, and Min Dong. 2014. “Cytotoxicity of Botulinum Neurotoxins Reveals a Direct Role of Syntaxin 1 and SNAP-25 in Neuron Survival.” Nature communications 4 (1): 1472. doi:10.1038/ncomms2462. http://dx.doi.org/10.1038/ncomms2462.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406680Botulinum neurotoxins (BoNT/A-G) are well-known to act by blocking synaptic vesicle exocytosis. Whether BoNTs disrupt additional neuronal functions has not been addressed. Here we report that cleavage of syntaxin 1 (Syx 1) by BoNT/C and cleavage of SNAP-25 by BoNT/E both induce degeneration of cultured rodent and human neurons. Furthermore, although SNAP-25 cleaved by BoNT/A can still support neuron survival, it has reduced capacity to tolerate additional mutations and also fails to pair with syntaxin isoforms other than Syx 1. Syx 1 and SNAP-25 are well-known for mediating synaptic vesicle exocytosis, but we found that neuronal death is due to blockage of plasma membrane recycling processes that share Syx 1/SNAP-25 for exocytosis, independent of blockage of synaptic vesicle exocytosis. These findings reveal neuronal cytotoxicity for a subset of BoNTs and directly link Syx 1/SNAP-25 to neuron survival as the prevalent SNARE proteins mediating multiple fusion events on neuronal plasma membranes.en-USJournal Article2014-07-0710.1038/ncomms2462