Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission.
Botulinum neurotoxin serotype C (BoNT/C) is a neuroparalytic toxin associated with outbreaks of animal botulism, particularly in birds, and is the only BoNT known to cleave two different SNARE proteins, SNAP-25 and syntaxin. BoNT/C was shown to be a good substitute for BoNT/A1 in human dystonia ther...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-08-01
|
| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC5568444?pdf=render |
| _version_ | 1818947162963181568 |
|---|---|
| author | Giulia Zanetti Stefan Sikorra Andreas Rummel Nadja Krez Elisa Duregotti Samuele Negro Tina Henke Ornella Rossetto Thomas Binz Marco Pirazzini |
| author_facet | Giulia Zanetti Stefan Sikorra Andreas Rummel Nadja Krez Elisa Duregotti Samuele Negro Tina Henke Ornella Rossetto Thomas Binz Marco Pirazzini |
| author_sort | Giulia Zanetti |
| collection | DOAJ |
| description | Botulinum neurotoxin serotype C (BoNT/C) is a neuroparalytic toxin associated with outbreaks of animal botulism, particularly in birds, and is the only BoNT known to cleave two different SNARE proteins, SNAP-25 and syntaxin. BoNT/C was shown to be a good substitute for BoNT/A1 in human dystonia therapy because of its long lasting effects and absence of neuromuscular damage. Two triple mutants of BoNT/C, namely BoNT/C S51T/R52N/N53P (BoNT/C α-51) and BoNT/C L200W/M221W/I226W (BoNT/C α-3W), were recently reported to selectively cleave syntaxin and have been used here to evaluate the individual contribution of SNAP-25 and syntaxin cleavage to the effect of BoNT/C in vivo. Although BoNT/C α-51 and BoNT/C α-3W toxins cleave syntaxin with similar efficiency, we unexpectedly found also cleavage of SNAP-25, although to a lesser extent than wild type BoNT/C. Interestingly, the BoNT/C mutants exhibit reduced lethality compared to wild type toxin, a result that correlated with their residual activity against SNAP-25. In spite of this, a local injection of BoNT/C α-51 persistently impairs neuromuscular junction activity. This is due to an initial phase in which SNAP-25 cleavage causes a complete blockade of neurotransmission, and to a second phase of incomplete impairment ascribable to syntaxin cleavage. Together, these results indicate that neuroparalysis of BoNT/C at the neuromuscular junction is due to SNAP-25 cleavage, while the proteolysis of syntaxin provides a substantial, but incomplete, neuromuscular impairment. In light of this evidence, we discuss a possible clinical use of BoNT/C α-51 as a botulinum neurotoxin endowed with a wide safety margin and a long lasting effect. |
| first_indexed | 2024-12-20T08:26:32Z |
| format | Article |
| id | doaj.art-709a8fb2f91a4d94a1032d899d60280d |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-20T08:26:32Z |
| publishDate | 2017-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-709a8fb2f91a4d94a1032d899d60280d2022-12-21T19:46:48ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-08-01138e100656710.1371/journal.ppat.1006567Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission.Giulia ZanettiStefan SikorraAndreas RummelNadja KrezElisa DuregottiSamuele NegroTina HenkeOrnella RossettoThomas BinzMarco PirazziniBotulinum neurotoxin serotype C (BoNT/C) is a neuroparalytic toxin associated with outbreaks of animal botulism, particularly in birds, and is the only BoNT known to cleave two different SNARE proteins, SNAP-25 and syntaxin. BoNT/C was shown to be a good substitute for BoNT/A1 in human dystonia therapy because of its long lasting effects and absence of neuromuscular damage. Two triple mutants of BoNT/C, namely BoNT/C S51T/R52N/N53P (BoNT/C α-51) and BoNT/C L200W/M221W/I226W (BoNT/C α-3W), were recently reported to selectively cleave syntaxin and have been used here to evaluate the individual contribution of SNAP-25 and syntaxin cleavage to the effect of BoNT/C in vivo. Although BoNT/C α-51 and BoNT/C α-3W toxins cleave syntaxin with similar efficiency, we unexpectedly found also cleavage of SNAP-25, although to a lesser extent than wild type BoNT/C. Interestingly, the BoNT/C mutants exhibit reduced lethality compared to wild type toxin, a result that correlated with their residual activity against SNAP-25. In spite of this, a local injection of BoNT/C α-51 persistently impairs neuromuscular junction activity. This is due to an initial phase in which SNAP-25 cleavage causes a complete blockade of neurotransmission, and to a second phase of incomplete impairment ascribable to syntaxin cleavage. Together, these results indicate that neuroparalysis of BoNT/C at the neuromuscular junction is due to SNAP-25 cleavage, while the proteolysis of syntaxin provides a substantial, but incomplete, neuromuscular impairment. In light of this evidence, we discuss a possible clinical use of BoNT/C α-51 as a botulinum neurotoxin endowed with a wide safety margin and a long lasting effect.http://europepmc.org/articles/PMC5568444?pdf=render |
| spellingShingle | Giulia Zanetti Stefan Sikorra Andreas Rummel Nadja Krez Elisa Duregotti Samuele Negro Tina Henke Ornella Rossetto Thomas Binz Marco Pirazzini Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission. PLoS Pathogens |
| title | Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission. |
| title_full | Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission. |
| title_fullStr | Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission. |
| title_full_unstemmed | Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission. |
| title_short | Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission. |
| title_sort | botulinum neurotoxin c mutants reveal different effects of syntaxin or snap 25 proteolysis on neuromuscular transmission |
| url | http://europepmc.org/articles/PMC5568444?pdf=render |
| work_keys_str_mv | AT giuliazanetti botulinumneurotoxincmutantsrevealdifferenteffectsofsyntaxinorsnap25proteolysisonneuromusculartransmission AT stefansikorra botulinumneurotoxincmutantsrevealdifferenteffectsofsyntaxinorsnap25proteolysisonneuromusculartransmission AT andreasrummel botulinumneurotoxincmutantsrevealdifferenteffectsofsyntaxinorsnap25proteolysisonneuromusculartransmission AT nadjakrez botulinumneurotoxincmutantsrevealdifferenteffectsofsyntaxinorsnap25proteolysisonneuromusculartransmission AT elisaduregotti botulinumneurotoxincmutantsrevealdifferenteffectsofsyntaxinorsnap25proteolysisonneuromusculartransmission AT samuelenegro botulinumneurotoxincmutantsrevealdifferenteffectsofsyntaxinorsnap25proteolysisonneuromusculartransmission AT tinahenke botulinumneurotoxincmutantsrevealdifferenteffectsofsyntaxinorsnap25proteolysisonneuromusculartransmission AT ornellarossetto botulinumneurotoxincmutantsrevealdifferenteffectsofsyntaxinorsnap25proteolysisonneuromusculartransmission AT thomasbinz botulinumneurotoxincmutantsrevealdifferenteffectsofsyntaxinorsnap25proteolysisonneuromusculartransmission AT marcopirazzini botulinumneurotoxincmutantsrevealdifferenteffectsofsyntaxinorsnap25proteolysisonneuromusculartransmission |