Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival
Botulinum toxins can cause substantial neurodegeneration. Peng et al . study cultured rat hippocampal neurons and find that botulinum toxin-induced cytotoxicity occurs only when there is effective cleavage of the SNARE proteins, syntaxin 1 or SNAP-25, by type C and type E botulinum toxins. Botulinum...
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Veröffentlicht in: | Nature communications 2013, Vol.4 (1), p.1472-1472, Article 1472 |
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Zusammenfassung: | Botulinum toxins can cause substantial neurodegeneration. Peng
et al
. study cultured rat hippocampal neurons and find that botulinum toxin-induced cytotoxicity occurs only when there is effective cleavage of the SNARE proteins, syntaxin 1 or SNAP-25, by type C and type E botulinum toxins.
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. |
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ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/ncomms2462 |