Special Delivery: Potential Mechanisms of Botulinum Neurotoxin Uptake and Trafficking within Motor Nerve Terminals
Botulinum neurotoxins (BoNTs) are highly potent, neuroparalytic protein toxins that block the release of acetylcholine from motor neurons and autonomic synapses. The unparalleled toxicity of BoNTs results from the highly specific and localized cleavage of presynaptic proteins required for nerve tran...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/22/8715 |
| _version_ | 1797547499066490880 |
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| author | Brittany M. Winner Skylar M. L. Bodt Patrick M. McNutt |
| author_facet | Brittany M. Winner Skylar M. L. Bodt Patrick M. McNutt |
| author_sort | Brittany M. Winner |
| collection | DOAJ |
| description | Botulinum neurotoxins (BoNTs) are highly potent, neuroparalytic protein toxins that block the release of acetylcholine from motor neurons and autonomic synapses. The unparalleled toxicity of BoNTs results from the highly specific and localized cleavage of presynaptic proteins required for nerve transmission. Currently, the only pharmacotherapy for botulism is prophylaxis with antitoxin, which becomes progressively less effective as symptoms develop. Treatment for symptomatic botulism is limited to supportive care and artificial ventilation until respiratory function spontaneously recovers, which can take weeks or longer. Mechanistic insights into intracellular toxin behavior have progressed significantly since it was shown that toxins exploit synaptic endocytosis for entry into the nerve terminal, but fundamental questions about host-toxin interactions remain unanswered. Chief among these are mechanisms by which BoNT is internalized into neurons and trafficked to sites of molecular toxicity. Elucidating how receptor-bound toxin is internalized and conditions under which the toxin light chain engages with target SNARE proteins is critical for understanding the dynamics of intoxication and identifying novel therapeutics. Here, we discuss the implications of newly discovered modes of synaptic vesicle recycling on BoNT uptake and intraneuronal trafficking. |
| first_indexed | 2024-03-10T14:45:57Z |
| format | Article |
| id | doaj.art-8ecab0e516224125ad0e479a4bbfe608 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:45:57Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8ecab0e516224125ad0e479a4bbfe6082023-11-20T21:25:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-012122871510.3390/ijms21228715Special Delivery: Potential Mechanisms of Botulinum Neurotoxin Uptake and Trafficking within Motor Nerve TerminalsBrittany M. Winner0Skylar M. L. Bodt1Patrick M. McNutt2United States Army Medical Research Institute of Chemical Defense, Gunpowder, MD 21047, USADepartment of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USAWake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC 27101, USABotulinum neurotoxins (BoNTs) are highly potent, neuroparalytic protein toxins that block the release of acetylcholine from motor neurons and autonomic synapses. The unparalleled toxicity of BoNTs results from the highly specific and localized cleavage of presynaptic proteins required for nerve transmission. Currently, the only pharmacotherapy for botulism is prophylaxis with antitoxin, which becomes progressively less effective as symptoms develop. Treatment for symptomatic botulism is limited to supportive care and artificial ventilation until respiratory function spontaneously recovers, which can take weeks or longer. Mechanistic insights into intracellular toxin behavior have progressed significantly since it was shown that toxins exploit synaptic endocytosis for entry into the nerve terminal, but fundamental questions about host-toxin interactions remain unanswered. Chief among these are mechanisms by which BoNT is internalized into neurons and trafficked to sites of molecular toxicity. Elucidating how receptor-bound toxin is internalized and conditions under which the toxin light chain engages with target SNARE proteins is critical for understanding the dynamics of intoxication and identifying novel therapeutics. Here, we discuss the implications of newly discovered modes of synaptic vesicle recycling on BoNT uptake and intraneuronal trafficking.https://www.mdpi.com/1422-0067/21/22/8715toxinsbotulinum neurotoxinsynaptic endocytosisbulk endosometranslocationsynaptic vesicles |
| spellingShingle | Brittany M. Winner Skylar M. L. Bodt Patrick M. McNutt Special Delivery: Potential Mechanisms of Botulinum Neurotoxin Uptake and Trafficking within Motor Nerve Terminals International Journal of Molecular Sciences toxins botulinum neurotoxin synaptic endocytosis bulk endosome translocation synaptic vesicles |
| title | Special Delivery: Potential Mechanisms of Botulinum Neurotoxin Uptake and Trafficking within Motor Nerve Terminals |
| title_full | Special Delivery: Potential Mechanisms of Botulinum Neurotoxin Uptake and Trafficking within Motor Nerve Terminals |
| title_fullStr | Special Delivery: Potential Mechanisms of Botulinum Neurotoxin Uptake and Trafficking within Motor Nerve Terminals |
| title_full_unstemmed | Special Delivery: Potential Mechanisms of Botulinum Neurotoxin Uptake and Trafficking within Motor Nerve Terminals |
| title_short | Special Delivery: Potential Mechanisms of Botulinum Neurotoxin Uptake and Trafficking within Motor Nerve Terminals |
| title_sort | special delivery potential mechanisms of botulinum neurotoxin uptake and trafficking within motor nerve terminals |
| topic | toxins botulinum neurotoxin synaptic endocytosis bulk endosome translocation synaptic vesicles |
| url | https://www.mdpi.com/1422-0067/21/22/8715 |
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