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...
Gespeichert in:
| Veröffentlicht in: | Nature communications 2013, Vol.4 (1), p.1472-1472, Article 1472 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext bestellen |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1472 |
|---|---|
| container_issue | 1 |
| container_start_page | 1472 |
| container_title | Nature communications |
| container_volume | 4 |
| creator | Peng, Lisheng Liu, Huisheng Ruan, Hongyu Tepp, William H. Stoothoff, William H. Brown, Robert H. Johnson, Eric A. Yao, Wei-Dong Zhang, Su-Chun Dong, Min |
| description | 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. |
| doi_str_mv | 10.1038/ncomms2462 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_C6C</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4052923</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2903632941</sourcerecordid><originalsourceid>FETCH-LOGICAL-c508t-695540c7cadbf4939542654e6edd1f0b2f2e1ee68a6d60a3e1c360ac64d20c2f3</originalsourceid><addsrcrecordid>eNplkV1LwzAUhoMoOuZu_AES8E6p5qvdeiOM4ReICup1SNPTrdImmqTF_XujmzoxBE7I--Q9h7wIHVBySgmfnBlt29YzkbEtNGBE0ISOGd_eOO-hkfcvJC6e04kQu2iPcUF4OuYDtJgtgw32vdZ1WGJb4cKGrqlN12IDnfuSjMcOelCNxwqXtQMdsLMNfOJ-aYKKCKZYmRI_3k0fEpbiePH13GDfub7uVbOPdqroAKN1HaLny4un2XVye391M5veJjolk5BkeZoKosdalUUlcp6ngmWpgAzKklakYBUDCpBNVFZmRHGgmseqM1EyolnFh-h85fvaFS2UGkxwqpGvrm6VW0qravlXMfVCzm0vBUlZzng0OFobOPvWgQ_yxXbOxJkl5ZTHr-NxD9HxitLOeu-g-ulAifwMRv4GE-HDzZl-0O8YInCyAnyUzBzcRs__dh_90pp8</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1313234334</pqid></control><display><type>article</type><title>Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival</title><source>Springer Nature OA Free Journals</source><creator>Peng, Lisheng ; Liu, Huisheng ; Ruan, Hongyu ; Tepp, William H. ; Stoothoff, William H. ; Brown, Robert H. ; Johnson, Eric A. ; Yao, Wei-Dong ; Zhang, Su-Chun ; Dong, Min</creator><creatorcontrib>Peng, Lisheng ; Liu, Huisheng ; Ruan, Hongyu ; Tepp, William H. ; Stoothoff, William H. ; Brown, Robert H. ; Johnson, Eric A. ; Yao, Wei-Dong ; Zhang, Su-Chun ; Dong, Min</creatorcontrib><description>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.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms2462</identifier><identifier>PMID: 23403573</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/326/41/1319 ; 631/378/1689/364 ; 631/378/87 ; 631/80/313/2104 ; 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 ; Humanities and Social Sciences ; Humans ; Molecular Sequence Data ; multidisciplinary ; Mutation - genetics ; Nerve Degeneration - metabolism ; Nerve Degeneration - pathology ; Neurons - drug effects ; Neurons - metabolism ; Neurons - pathology ; Neurotoxins - chemistry ; Neurotoxins - toxicity ; Protein Structure, Tertiary ; Rats ; Science ; Science (multidisciplinary) ; Synaptic Vesicles - drug effects ; Synaptic Vesicles - metabolism ; Synaptosomal-Associated Protein 25 - genetics ; Synaptosomal-Associated Protein 25 - metabolism ; Syntaxin 1 - chemistry ; Syntaxin 1 - metabolism</subject><ispartof>Nature communications, 2013, Vol.4 (1), p.1472-1472, Article 1472</ispartof><rights>Springer Nature Limited 2013</rights><rights>Copyright Nature Publishing Group Feb 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-695540c7cadbf4939542654e6edd1f0b2f2e1ee68a6d60a3e1c360ac64d20c2f3</citedby><cites>FETCH-LOGICAL-c508t-695540c7cadbf4939542654e6edd1f0b2f2e1ee68a6d60a3e1c360ac64d20c2f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052923/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052923/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,4024,27923,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.1038/ncomms2462$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23403573$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Peng, Lisheng</creatorcontrib><creatorcontrib>Liu, Huisheng</creatorcontrib><creatorcontrib>Ruan, Hongyu</creatorcontrib><creatorcontrib>Tepp, William H.</creatorcontrib><creatorcontrib>Stoothoff, William H.</creatorcontrib><creatorcontrib>Brown, Robert H.</creatorcontrib><creatorcontrib>Johnson, Eric A.</creatorcontrib><creatorcontrib>Yao, Wei-Dong</creatorcontrib><creatorcontrib>Zhang, Su-Chun</creatorcontrib><creatorcontrib>Dong, Min</creatorcontrib><title>Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>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.</description><subject>631/326/41/1319</subject><subject>631/378/1689/364</subject><subject>631/378/87</subject><subject>631/80/313/2104</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Botulinum Toxins - chemistry</subject><subject>Botulinum Toxins - toxicity</subject><subject>Cell Death - drug effects</subject><subject>Cell Membrane - drug effects</subject><subject>Cell Membrane - metabolism</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Endocytosis - drug effects</subject><subject>Exocytosis - drug effects</subject><subject>HEK293 Cells</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Molecular Sequence Data</subject><subject>multidisciplinary</subject><subject>Mutation - genetics</subject><subject>Nerve Degeneration - metabolism</subject><subject>Nerve Degeneration - pathology</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Neurotoxins - chemistry</subject><subject>Neurotoxins - toxicity</subject><subject>Protein Structure, Tertiary</subject><subject>Rats</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Synaptic Vesicles - drug effects</subject><subject>Synaptic Vesicles - metabolism</subject><subject>Synaptosomal-Associated Protein 25 - genetics</subject><subject>Synaptosomal-Associated Protein 25 - metabolism</subject><subject>Syntaxin 1 - chemistry</subject><subject>Syntaxin 1 - metabolism</subject><issn>2041-1723</issn><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNplkV1LwzAUhoMoOuZu_AES8E6p5qvdeiOM4ReICup1SNPTrdImmqTF_XujmzoxBE7I--Q9h7wIHVBySgmfnBlt29YzkbEtNGBE0ISOGd_eOO-hkfcvJC6e04kQu2iPcUF4OuYDtJgtgw32vdZ1WGJb4cKGrqlN12IDnfuSjMcOelCNxwqXtQMdsLMNfOJ-aYKKCKZYmRI_3k0fEpbiePH13GDfub7uVbOPdqroAKN1HaLny4un2XVye391M5veJjolk5BkeZoKosdalUUlcp6ngmWpgAzKklakYBUDCpBNVFZmRHGgmseqM1EyolnFh-h85fvaFS2UGkxwqpGvrm6VW0qravlXMfVCzm0vBUlZzng0OFobOPvWgQ_yxXbOxJkl5ZTHr-NxD9HxitLOeu-g-ulAifwMRv4GE-HDzZl-0O8YInCyAnyUzBzcRs__dh_90pp8</recordid><startdate>2013</startdate><enddate>2013</enddate><creator>Peng, Lisheng</creator><creator>Liu, Huisheng</creator><creator>Ruan, Hongyu</creator><creator>Tepp, William H.</creator><creator>Stoothoff, William H.</creator><creator>Brown, Robert H.</creator><creator>Johnson, Eric A.</creator><creator>Yao, Wei-Dong</creator><creator>Zhang, Su-Chun</creator><creator>Dong, Min</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>SOI</scope><scope>5PM</scope></search><sort><creationdate>2013</creationdate><title>Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival</title><author>Peng, Lisheng ; Liu, Huisheng ; Ruan, Hongyu ; Tepp, William H. ; Stoothoff, William H. ; Brown, Robert H. ; Johnson, Eric A. ; Yao, Wei-Dong ; Zhang, Su-Chun ; Dong, Min</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-695540c7cadbf4939542654e6edd1f0b2f2e1ee68a6d60a3e1c360ac64d20c2f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>631/326/41/1319</topic><topic>631/378/1689/364</topic><topic>631/378/87</topic><topic>631/80/313/2104</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Botulinum Toxins - chemistry</topic><topic>Botulinum Toxins - toxicity</topic><topic>Cell Death - drug effects</topic><topic>Cell Membrane - drug effects</topic><topic>Cell Membrane - metabolism</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Endocytosis - drug effects</topic><topic>Exocytosis - drug effects</topic><topic>HEK293 Cells</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Molecular Sequence Data</topic><topic>multidisciplinary</topic><topic>Mutation - genetics</topic><topic>Nerve Degeneration - metabolism</topic><topic>Nerve Degeneration - pathology</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Neurotoxins - chemistry</topic><topic>Neurotoxins - toxicity</topic><topic>Protein Structure, Tertiary</topic><topic>Rats</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Synaptic Vesicles - drug effects</topic><topic>Synaptic Vesicles - metabolism</topic><topic>Synaptosomal-Associated Protein 25 - genetics</topic><topic>Synaptosomal-Associated Protein 25 - metabolism</topic><topic>Syntaxin 1 - chemistry</topic><topic>Syntaxin 1 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Peng, Lisheng</creatorcontrib><creatorcontrib>Liu, Huisheng</creatorcontrib><creatorcontrib>Ruan, Hongyu</creatorcontrib><creatorcontrib>Tepp, William H.</creatorcontrib><creatorcontrib>Stoothoff, William H.</creatorcontrib><creatorcontrib>Brown, Robert H.</creatorcontrib><creatorcontrib>Johnson, Eric A.</creatorcontrib><creatorcontrib>Yao, Wei-Dong</creatorcontrib><creatorcontrib>Zhang, Su-Chun</creatorcontrib><creatorcontrib>Dong, Min</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Environment Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Biological Science Journals</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>Environment Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Peng, Lisheng</au><au>Liu, Huisheng</au><au>Ruan, Hongyu</au><au>Tepp, William H.</au><au>Stoothoff, William H.</au><au>Brown, Robert H.</au><au>Johnson, Eric A.</au><au>Yao, Wei-Dong</au><au>Zhang, Su-Chun</au><au>Dong, Min</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2013</date><risdate>2013</risdate><volume>4</volume><issue>1</issue><spage>1472</spage><epage>1472</epage><pages>1472-1472</pages><artnum>1472</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>23403573</pmid><doi>10.1038/ncomms2462</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext_linktorsrc |
| identifier | ISSN: 2041-1723 |
| ispartof | Nature communications, 2013, Vol.4 (1), p.1472-1472, Article 1472 |
| issn | 2041-1723 2041-1723 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4052923 |
| source | Springer Nature OA Free Journals |
| subjects | 631/326/41/1319 631/378/1689/364 631/378/87 631/80/313/2104 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 Humanities and Social Sciences Humans Molecular Sequence Data multidisciplinary Mutation - genetics Nerve Degeneration - metabolism Nerve Degeneration - pathology Neurons - drug effects Neurons - metabolism Neurons - pathology Neurotoxins - chemistry Neurotoxins - toxicity Protein Structure, Tertiary Rats Science Science (multidisciplinary) Synaptic Vesicles - drug effects Synaptic Vesicles - metabolism Synaptosomal-Associated Protein 25 - genetics Synaptosomal-Associated Protein 25 - metabolism Syntaxin 1 - chemistry Syntaxin 1 - metabolism |
| title | Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T06%3A11%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_C6C&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cytotoxicity%20of%20botulinum%20neurotoxins%20reveals%20a%20direct%20role%20of%20syntaxin%201%20and%20SNAP-25%20in%20neuron%20survival&rft.jtitle=Nature%20communications&rft.au=Peng,%20Lisheng&rft.date=2013&rft.volume=4&rft.issue=1&rft.spage=1472&rft.epage=1472&rft.pages=1472-1472&rft.artnum=1472&rft.issn=2041-1723&rft.eissn=2041-1723&rft_id=info:doi/10.1038/ncomms2462&rft_dat=%3Cproquest_C6C%3E2903632941%3C/proquest_C6C%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1313234334&rft_id=info:pmid/23403573&rfr_iscdi=true |