title: Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival.
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.
authors: Department of Microbiology and Immunobiology, Harvard Medical School, Division of Neuroscience, New England Primate Research Center, Southborough, Massachusetts 01772, USA.
authors: Lisheng
authors: L
authors: Peng
authors: Huisheng
authors: H
authors: Liu
authors: Hongyu
authors: H
authors: Ruan
authors: William H
authors: WH
authors: Tepp
authors: William H
authors: WH
authors: Stoothoff
authors: Robert H
authors: RH
authors: Brown
authors: Eric A
authors: EA
authors: Johnson
authors: Wei-Dong
authors: WD
authors: Yao
authors: Su-Chun
authors: SC
authors: Zhang
authors: Min
authors: M
authors: Dong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001905:Botulinum Toxins / Q000737:chemistry / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009498:Neurotoxins / Q000737:chemistry / Q000633:toxicity*; D017434:Protein Structure, Tertiary; D051381:Rats; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism*; D050827:Syntaxin 1 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D009498:Neurotoxins; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D001905:Botulinum Toxins
references: Annu Rev Biochem. 2009;78:857-902
references: 19317650
references: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):9037-42
references: 12070347
references: Nat Cell Biol. 2011 Jan;13(1):30-9
references: 21151134
references: Science. 2010 Sep 24;329(5999):1663-7
references: 20798282
references: Genetics. 1996 Dec;144(4):1713-24
references: 8978057
references: Nature. 1998 Sep 24;395(6700):347-53
references: 9759724
references: Science. 2000 Feb 4;287(5454):864-9
references: 10657302
references: EMBO J. 2010 Aug 4;29(15):2477-90
references: 20562829
references: J Neurosci. 2001 Dec 1;21(23):9142-50
references: 11717347
references: J Neurosci. 2010 Jan 6;30(1):242-54
references: 20053906
references: Physiol Rev. 2000 Apr;80(2):717-66
references: 10747206
references: J Cell Biol. 1996 Jul;134(1):205-15
references: 8698815
references: J Neurosci. 2007 Aug 29;27(35):9380-91
references: 17728451
references: EMBO J. 1993 Dec;12(12):4821-8
references: 7901002
references: Nat Rev Mol Cell Biol. 2006 Sep;7(9):631-43
references: 16912714
references: EMBO J. 2012 Feb 15;31(4):829-41
references: 22187053
references: J Neurosci. 2006 Jul 26;26(30):7826-38
references: 16870728
references: PLoS Pathog. 2011 Mar;7(3):e1002008
references: 21483489
references: J Cell Biol. 2005 Feb 14;168(4):607-18
references: 15716378
references: J Biol Chem. 1995 May 5;270(18):10566-70
references: 7737992
references: J Neurochem. 1986 Sep;47(3):930-7
references: 3734804
references: Neuron. 1995 May;14(5):991-8
references: 7748566
references: J Biol Chem. 1993 Nov 15;268(32):23784-7
references: 8226912
references: Neuron. 2009 Aug 13;63(3):357-71
references: 19679075
references: Biochem Biophys Res Commun. 2008 Oct 24;375(3):372-7
references: 18713622
references: Brain Res Bull. 2001 Sep 15;56(2):111-7
references: 11704347
references: Neuropharmacology. 1995 Nov;34(11):1351-60
references: 8606784
references: ScientificWorldJournal. 2009 Dec 16;9:1463-75
references: 20024519
references: J Cell Biol. 1997 Aug 25;138(4):861-75
references: 9265652
references: J Neurochem. 1999 Jan;72(1):327-37
references: 9886085
references: Genetics. 1999 Aug;152(4):1631-9
references: 10430588
references: Nat Protoc. 2009;4(9):1295-304
references: 19696748
references: Biochemistry. 2011 Apr 12;50(14):2711-3
references: 21401123
references: Annu Rev Biochem. 2010;79:591-617
references: 20233039
references: Neuroreport. 2010 Jan 6;21(1):14-18
references: 19907349
references: Nature. 1995 Dec 7;378(6557):623-6
references: 8524397
references: J Neurosci Res. 1998 Jun 1;52(5):569-83
references: 9632313
references: Am J Hum Genet. 2011 Aug 12;89(2):241-52
references: 21820099
references: Neuron. 2004 Feb 19;41(4):599-610
references: 14980208
references: Nat Neurosci. 2002 Jan;5(1):19-26
references: 11753414
references: J Neurochem. 2007 Oct;103(1):115-23
references: 17877635
references: Biochemistry. 1996 Feb 27;35(8):2630-6
references: 8611567
references: Eur J Neurosci. 2004 Aug;20(3):623-34
references: 15255974
references: Nature. 1993 Sep 9;365(6442):160-3
references: 8103915
references: Cell. 1995 Jan 27;80(2):311-20
references: 7834751
references: Science. 2009 Jan 23;323(5913):474-7
references: 19164740
references: J Comp Neurol. 1996 Apr 01;367(2):222-34
references: 8708006
references: J Gen Microbiol. 1987 Sep;133(9):2647-57
references: 3329217
references: J Biol Chem. 1996 Jun 7;271(23):13300-3
references: 8663154
references: J Biol Chem. 2010 Aug 6;285(32):24968-76
references: 20522554
references: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15781-6
references: 9861047
references: Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5247-51
references: 1711221
references: J Biol Chem. 2003 Jan 10;278(2):1363-71
references: 12381720
references: J Biol Chem. 2003 Apr 11;278(15):12796-804
references: 12562778
references: EMBO J. 2006 Mar 8;25(5):955-66
references: 16498411