SNARE proteins are the essential machinery of eukaryotic membrane fusion in the secretory and endocytic pathways. These neuronal proteins have found to be targets of the tetanus and botulinum toxins, highlighting their importance in synaptic vesicle fusion and neurotransmitter release. (Yoon & Munson, 2018)
The primary role of SNARE proteins is to mediate vesicle fusion, that is, the fusion of vesicles with their target membrane-bound compartments (such as a lysosome). SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis, and, by directly interacting with different calcium channels subunits, it negatively modulates neuronal voltage-gated calcium channels, thus regulating intracellular calcium dynamics. The SNAP-25 gene has been associated with distinct brain diseases, including Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia and bipolar disorder, indicating that the protein may act as a shared biological substrate among different “synaptopathies”. (Antonucci et al, 2016)
Tetanus and botulinum neurotoxins cause the neuroparalytic syndromes of tetanus and botulism, respectively, by delivering inside different types of neurons, metalloproteases specifically cleaving the SNARE proteins that are essential for the release of neurotransmitters. (Pirazzine et al, 2022)
Following injection into tissues, onabotulinumtoxinA inhibits soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE)-mediated vesicle trafficking by cleaving one of its essential proteins, soluble N-ethylmaleimide-sensitive fusion attachment protein (SNAP-25), which occurs in both motor and sensory nerves. OnabotulinumtoxinA inhibits regulated exocytosis of motor and sensory neurochemicals and proteins, as well as membrane insertion of peripheral receptors that convey pain from the periphery to the brain, because both processes are SNARE dependent. (Burstein et al, 2020)
Different serotypes of botulinum toxins (BoNTs) act upon different types of SNARE proteins. This property is used in aesthetic medicine to treat certain eye disorders such as crossed eyes (strabismus) and uncontrolled blinking (blepharospasm), to treat muscle spasms or movement disorders, and, for the two last decades, more and more often, to provide support in cancer therapy, especially so as to obtain analgesic effects upon spastic conditions. (Grenda et al, 2022)
Yoon TY, Munson M. SNARE complex assembly and disassembly. Curr Biol. 2018 Apr 23;28(8):R397-R401. doi: 10.1016/j.cub.2018.01.005. PMID: 29689222.
Antonucci F, Corradini I, Fossati G, Tomasoni R, Menna E, Matteoli M. SNAP-25, a Known Presynaptic Protein with Emerging Postsynaptic Functions. Front Synaptic Neurosci. 2016 Mar 24;8:7. doi: 10.3389/fnsyn.2016.00007. PMID: 27047369; PMCID: PMC4805587.
Pirazzini M, Montecucco C, Rossetto O. Toxicology and pharmacology of botulinum and tetanus neurotoxins: an update. Arch Toxicol. 2022 Jun;96(6):1521-1539. doi: 10.1007/s00204-022-03271-9. Epub 2022 Mar 25. PMID: 35333944; PMCID: PMC9095541.
Burstein R, Blumenfeld AM, Silberstein SD, Manack Adams A, Brin MF. Mechanism of Action of OnabotulinumtoxinA in Chronic Migraine: A Narrative Review. Headache. 2020 Jul;60(7):1259-1272. doi: 10.1111/head.13849. Epub 2020 Jun 30. PMID: 32602955; PMCID: PMC7496564.
Grenda T, Grenda A, Krawczyk P, Kwiatek K. Botulinum toxin in cancer therapy-current perspectives and limitations. Appl Microbiol Biotechnol. 2022 Jan;106(2):485-495. doi: 10.1007/s00253-021-11741-w. Epub 2021 Dec 24. PMID: 34951660; PMCID: PMC8763801.