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

Nat Commun. 2013;4:1472. doi: 10.1038/ncomms2462.

Abstract

Botulinum neurotoxins (BoNT/A-G) act by blocking synaptic vesicle exocytosis. Whether BoNTs disrupt additional neuronal functions has not been addressed. Here we report that cleavage of syntaxin 1 by BoNT/C, and cleavage of SNAP-25 by BoNT/E both induce degeneration of neurons. Furthermore, although SNAP-25 cleaved by BoNT/A still supports neuron survival, it has reduced capacity to tolerate additional mutations. We demonstrate that 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 and prevent toxin-induced neuron death. Finally, we find that neuronal death is due to blockage of plasma membrane recycling processes that utilize syntaxin 1/SNAP-25, independent of synaptic vesicle exocytosis. These findings establish neuronal cytotoxicity for BoNTs and reveal syntaxin 1/SNAP-25 as the ubiquitous and essential SNARE proteins mediating multiple fusion events on neuronal plasma membranes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Botulinum Toxins / chemistry
  • Botulinum Toxins / toxicity*
  • Cell Death / drug effects
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Endocytosis / drug effects
  • Exocytosis / drug effects
  • HEK293 Cells
  • Humans
  • Molecular Sequence Data
  • Mutation / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology*
  • Neurotoxins / chemistry
  • Neurotoxins / toxicity*
  • Protein Structure, Tertiary
  • Rats
  • Synaptic Vesicles / drug effects
  • Synaptic Vesicles / metabolism
  • Synaptosomal-Associated Protein 25 / genetics
  • Synaptosomal-Associated Protein 25 / metabolism*
  • Syntaxin 1 / chemistry
  • Syntaxin 1 / metabolism*

Substances

  • Neurotoxins
  • Synaptosomal-Associated Protein 25
  • Syntaxin 1
  • Botulinum Toxins