Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Skip to main content
SpringerLink
Log in

Tetanus and Botulinum Neurotoxins

  • Living reference work entry
  • First Online:
Microbial Toxins

Part of the book series: Toxinology ((TOXI))

  • 956 Accesses

Abstract

Tetanus and botulinum neurotoxins are clostridial toxins that cause tetanus and botulism, respectively. Tetanus neurotoxin binds specifically to peripheral motoneuron nerve terminals at the neuromuscular junction and is endocytosed within vesicles, which transport the toxin retroaxonally to the spinal cord. Here, it enters the inhibitory interneurons that ensure the balanced contraction of opposing skeletal muscle, and the metalloprotease domain of the toxin inactivates VAMP/synaptobrevin, a protein essential for neurotransmitter release. The synapse of the inhibitory circuit at the spinal cord is blocked resulting in a characteristic spastic paralysis. The botulinum neurotoxins are produced in dozens of different isoforms that can be grouped into seven distinct serotypes. They bind to neurospecific receptors enriched in the presynaptic membrane of cholinergic nerve terminals and are then mainly internalized inside the synaptic vesicles wherefrom their metalloprotease domain translocates in the cytosol and cleaves one of the three SNARE proteins that form the core of the nanomachine which mediates the neuroexocytosis with ensuing flaccid paralysis. In spite of the opposing clinical symptoms, botulinum and tetanus neurotoxins intoxicate neuronal cells in the same way and have similar functional and structural organizations. Common features and molecular diversities between tetanus and botulinum neurotoxin mechanism of action will be discussed in this present chapter.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References

  • Araye, A., Goudet, A., Barbier, J., Pichard, S., Baron, B., England, P., Perez, J., Zinn-Justin, S., Chenal, A., & Gillet, D. (2016). The translocation domain of botulinum neurotoxin a moderates the propensity of the catalytic domain to interact with membranes at acidic pH. PLoS One, 11(4), e0153401.

    Article  PubMed  PubMed Central  Google Scholar 

  • Benefield, D. A., Dessain, S. K., Shine, N., Ohi, M. D., & Lacy, D. B. (2013). Molecular assembly of botulinum neurotoxin progenitor complexes. Proc Natl Acad Sci U S A, 110, 5630–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bercsenyi, K., Schmieg, N., Bryson, J. B., Wallace, M., Caccin, P., Golding, M., et al. (2014). Tetanus toxin entry. Nidogens are therapeutic targets for the prevention of tetanus. Science, 346, 1118–23.

    Article  CAS  PubMed  Google Scholar 

  • Binz, T., & Rummel, A. (2009). Cell entry strategy of clostridial neurotoxins. J Neurochem, 109, 1584–95.

    Article  CAS  PubMed  Google Scholar 

  • Bilsland, L. G., Sahai, E., Kelly, G., Golding, M., Greensmith, L., & Schiavo, G. (2010). Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci U S A, 107(47), 20523–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bizzini, B., Grob, P., & Akert, K. (1981). Papain-derived fragment IIc of tetanus toxin: its binding to isolated synaptic membranes and retrograde axonal transport. Brain Res, 210, 291–9.

    Article  CAS  PubMed  Google Scholar 

  • Bohnert, S., & Schiavo, G. (2005). Tetanus toxin is transported in a novel neuronal compartment characterized by a specialized pH regulation. J Biol Chem, 280, 42336–44.

    Article  CAS  PubMed  Google Scholar 

  • Breidenbach, M. A., & Brunger, A. T. (2005). 2.3 A crystal structure of tetanus neurotoxin light chain. Biochemistry, 44(20), 7450–7.

    Article  CAS  PubMed  Google Scholar 

  • Bruggemann, H., Baumer, S., Fricke, W. F., Wiezer, A., Liesegang, H., Decker, I., Herzberg, C., Martinez-Arias, R., Merkl, R., Henne, A., & Gottschalk, G. (2003). The genome sequence of Clostridium tetani, the causative agent of tetanus disease. Proc Natl Acad Sci USA, 100, 1316–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaddock, J. (2013). Transforming the domain structure of botulinum neurotoxins into novel therapeutics. Curr Top Microbiol Immunol, 364, 287–306.

    PubMed  Google Scholar 

  • Chen, S. (2014). Clostridial neurotoxins: mode of substrate recognition and novel therapy development. Curr Protein Pept Sci, 15(5), 490–503.

    Article  CAS  PubMed  Google Scholar 

  • Colasante, C., Rossetto, O., Morbiato, L., Pirazzini, M., Molgo, J., & Montecucco, C. (2013). Botulinum neurotoxin type A is internalized and translocated from small synaptic vesicles at the neuromuscular junction. Mol Neurobiol, 48, 120–7.

    Article  CAS  PubMed  Google Scholar 

  • Comella, J. X., Molgó, J., & Faille, L. (1993). Sprouting of mammalian motor nerve terminals induced by in vivo injection of botulinum type D toxin and the functional recovery of paralysed neuromuscular junctions. Neurosci Lett, 153, 61–4.

    Article  CAS  PubMed  Google Scholar 

  • Eisele, K. H., Fink, K., Vey, M., & Taylor, H. V. (2011). Studies on the dissociation of botulinum neurotoxin type A complexes. Toxicon, 57, 555–65.

    Article  CAS  PubMed  Google Scholar 

  • Eleopra, R., Tugnoli, V., Quatrale, R., Rossetto, O., & Montecucco, C. (2004). Different types of botulinum toxin in humans. Mov Disord, 19, S53–9.

    Article  PubMed  Google Scholar 

  • Fischer, A., & Montal, M. (2013). Molecular dissection of botulinum neurotoxin reveals interdomain chaperone function. Toxicon, 75, 101–7.

    Article  CAS  PubMed  Google Scholar 

  • Foran, P. G., Mohammed, N., Lisk, G. O., Nagwaney, S., Lawrence, G. W., Johnson, E., et al. (2003). Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long-lasting type A. J Biol Chem, 278, 1363–71.

    Article  CAS  PubMed  Google Scholar 

  • Foster, K. A. (2014). Clinical applications of botulinum neurotoxin (Current topics in neurotoxicity). New York: Springer.

    Book  Google Scholar 

  • Fujinaga, Y., Sugawara, Y., & Matsumura, T. (2013). Uptake of botulinum neurotoxin in the intestine. Curr Top Microbiol Immunol, 364, 45–59.

    CAS  PubMed  Google Scholar 

  • Georgiou, J., Robitaille, R., Trimble, W. S., & Charlton, M. P. (1994). Synaptic regulation of glial protein expression in vivo. Neuron, 12, 443–55.

    Article  CAS  PubMed  Google Scholar 

  • Hallett, M., Albanese, A., Dressler, D., Segal, K. R., Simpson, D. M., Truong, D., & Jankovic, J. (2013). Evidence-based review and assessment of botulinum neurotoxin for the treatment of movement disorders. Toxicon, 67, 94–114.

    Article  CAS  PubMed  Google Scholar 

  • Harper, C. B., Martin, S., Nguyen, T. H., Daniels, S. J., Lavidis, N. A., Popoff, M. R., Hadzic, G., Mariana, A., Chau, N., McCluskey, A., Robinson, P. J., & Meunier, F. A. (2011). Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism. J Biol Chem, 286, 35966–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hughes, R., & Whaler, B. C. (1962). Influence of nerve-ending activity and of drugs on the rate of paralysis of rat diaphragm preparations by Cl. botulinum type A toxin. J Physiol, 160, 221–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson, E. A., & Montecucco, C. (2008). Botulism. Handb Clin Neurol, 91, 333–68.

    Article  PubMed  Google Scholar 

  • Juzans, P., Comella, J. X., Molgó, J., Faille, L., & Angaut-Petit, D. (1996). Nerve terminal sprouting in botulinum type-A treated mouse levator auris longus muscle. Neuromuscul Disord, 6, 177–85.

    Article  CAS  PubMed  Google Scholar 

  • Kalb, S. R., Baudys, J., Raphael, B. H., Dykes, J. K., Luquez, C., Maslanka, S. E., & Barr, J. R. (2015). Functional characterization of botulinum neurotoxin serotype H as a hybrid of known serotypes F and A (BoNT F/A). Anal Chem, 87(7), 3911–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalb, S. R., Baudys, J., Webb, R. P., Wright, P., Smith, T. J., Smith, L. A., Fernandez, R., Raphael, B. H., Maslanka, S. E., Pirkle, J. L., & Barr, J. R. (2012). Discovery of a novel enzymatic cleavage site for botulinum neurotoxin F5. FEBS Lett, 586(2), 109–15.

    Article  CAS  PubMed  Google Scholar 

  • Keller, J. E., Cai, F., & Neale, E. A. (2004). Uptake of botulinum neurotoxin into cultured neurons. Biochemistry, 43(2), 526–32.

    Article  CAS  PubMed  Google Scholar 

  • Keller, J. E., Neale, E. A., Oyler, G., & Adler, M. (1999). Persistence of botulinum neurotoxin action in cultured spinal cord cells. FEBS Lett, 456, 137–42.

    Article  CAS  PubMed  Google Scholar 

  • Kitamura, M., Igimi, S., Furukawa, K., & Furukawa, K. (2005). Different response of the knockout mice lacking b-series gangliosides against botulinum and tetanus toxins. Biochim Biophys Acta, 1741(1-2), 1–3.

    Article  CAS  PubMed  Google Scholar 

  • Kumaran, D., Eswaramoorthy, S., Furey, W., Navaza, J., Sax, M., & Swaminathan, S. (2009). Domain organization in clostridium botulinum neurotoxin type E is unique: its implication in faster translocation. J Mol Biol, 386(1), 233–45.

    Article  CAS  PubMed  Google Scholar 

  • Lacy, D., Tepp, W., Cohen, A., DasGupta, B., & Stevens, R. (1998). Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Mol Biol, 5(10), 898–902.

    Article  CAS  Google Scholar 

  • Lee, K., Gu, S., Jin, L., Le, T., Cheng, L., Strotmeier, J., et al. (2013). Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLoS Pathog, 9(10), e1003690.

    Article  PubMed  PubMed Central  Google Scholar 

  • Masuyer, G., Chaddock, J. A., Foster, K. A., & Acharya, K. R. (2014). Engineered botulinum neurotoxins as new therapeutics. Annu Rev Pharmacol Toxicol, 54, 27–51.

    Article  CAS  PubMed  Google Scholar 

  • Matteoli, M., Verderio, C., Rossetto, O., Iezzi, N., Coco, S., Schiavo, G., & Montecucco, C. (1996). Synaptic vesicle endocytosis mediates the entry of tetanus neurotoxin into hippocampal neurons. Proc Natl Acad Sci U S A, 93(23), 13310–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mazzocchio, R., & Caleo, M. (2015). More than at the neuromuscular synapse: actions of botulinum neurotoxin A in the central nervous system. Neuroscientist, 21, 44–61.

    Article  PubMed  Google Scholar 

  • Megighian, A., Zordan, M., Pantano, S., Scorzeto, M., Rigoni, M., Zanini, D., Rossetto, O., & Montecucco, C. (2013). Evidence for a radial SNARE super-complex mediating neurotransmitter release at the Drosophila neuromuscular junction. J Cell Sci, 126, 3134–40.

    Article  CAS  PubMed  Google Scholar 

  • Meunier, F. A., Lisk, G., Sesardic, D., & Dolly, J. O. (2003). Dynamics of motor nerve terminal remodeling unveiled using SNARE-cleaving botulinum toxins: the extent and duration are dictated by the sites of SNAP-25 truncation. Mol Cell Neurosci, 22, 454–66.

    Article  CAS  PubMed  Google Scholar 

  • Montal, M. (2010). Botulinum neurotoxin: a marvel of protein design. Annu Rev Biochem, 79, 591–617.

    Article  CAS  PubMed  Google Scholar 

  • Montecucco, C. (1986). How do tetanus and botulinum toxins bind to neuronal membranes? Trends Biochem Sci, 11, 314–7.

    Article  CAS  Google Scholar 

  • Montecucco, C., & Rasotto, M. (2015). On botulinum neurotoxin variability. mBio, 6(1), e02131–.

    Google Scholar 

  • Morbiato, L., Carli, L., Johnson, E. A., Montecucco, C., Molgo, J., & Rossetto, O. (2007). Neuromuscular paralysis and recovery in mice injected with botulinum neurotoxins A and C. Eur J Neurosci, 25(9), 2697–704.

    Article  PubMed  Google Scholar 

  • Muraro, L., Tosatto, S., Motterlini, L., Rossetto, O., & Montecucco, C. (2009). The N-terminal half of the receptor domain of botulinum neurotoxin A binds to microdomains of the plasma membrane. Biochem Biophys Res Commun, 380, 76–80.

    Article  CAS  PubMed  Google Scholar 

  • Pantano, S., & Montecucco, C. (2014). The blockade of the neurotransmitter release apparatus by botulinum neurotoxins. Cell Mol Life Sci, 71(5), 793–811.

    Article  CAS  PubMed  Google Scholar 

  • Pirazzini, M., Bordin, F., Rossetto, O., Shone, C. C., Binz, T., & Montecucco, C. (2013a). The thioredoxin reductase-thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals. FEBS Lett, 587, 150–5.

    Article  CAS  PubMed  Google Scholar 

  • Pirazzini, M., Rossetto, O., Bertasio, C., Bordin, F., Shone, C., Binz, T., et al. (2013b). Time course and temperature dependence of the membrane translocation of tetanus and botulinum neurotoxins C and D in neurons. Biochem Biophys Res Commun, 430(1), 38–42.

    Article  CAS  PubMed  Google Scholar 

  • Pirazzini, M., Rossetto, O., Bolognese, P., Shone, C. C., & Montecucco, C. (2011). Double anchorage to the membrane and intact inter-chain disulfide bond are required for the low pH induced entry of tetanus and botulinum neurotoxins into neurons. Cell Microbiol, 13, 1731–43.

    Article  CAS  PubMed  Google Scholar 

  • Pirazzini, M., Tehran, D., Leka, O., Zanetti, G., Rossetto, O., & Montecucco, C. (2016). On the translocation of botulinum and tetanus neurotoxins across the membrane of acidic intracellular compartments. Biochim Biophys Acta, 1858(3), 467–74.

    Article  CAS  PubMed  Google Scholar 

  • Popoff, M. R., & Marvaud, J. C. (1999). Structural and genomic features of clostridial neurotoxins. In J. E. Alouf & J. H. Freer (Eds.), The comprehensive sourcebook of bacterial protein toxins (2nd ed., pp. 174–201). London: Academic.

    Google Scholar 

  • Restani, L., Giribaldi, F., Manich, M., Bercsenyi, K., Menendez, G., Rossetto, O., Caleo, M., & Schiavo, G. (2012). Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons. PLoS Pathog, 8, e1003087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossetto, O., Pirazzini, M., & Montecucco, C. (2014). Botulinum neurotoxins: genetic, structural and mechanistic insights. Nat Rev Microbiol, 12(8), 535–49.

    Article  CAS  PubMed  Google Scholar 

  • Rossetto, O., Schiavo, G., Montecucco, C., Poulain, B., Deloye, F., Lozzi, L., & Shone, C. C. (1994). SNARE motif and neurotoxins. Nature, 372(6505), 415–6.

    Article  CAS  PubMed  Google Scholar 

  • Rummel, A. (2013). Double receptor anchorage of botulinum neurotoxins accounts for their exquisite neurospecificity. Curr Top Microbiol Immunol, 364, 61–90.

    CAS  PubMed  Google Scholar 

  • Schmitt, A., Dreyer, F., & John, C. (1981). At least three sequential steps are involved in the tetanus toxin induced block of neuromuscular transmission. Naunyn Schmiedebergs Arch Pharmacol, 317, 326–30.

    Article  CAS  PubMed  Google Scholar 

  • Schmieg, N., Bercsenyi, K., & Schiavo, G. (2015). Uptake and transport of clostridial neurotoxins. In J. E. Alouf, D. Ladant, & M. R. Popoff (Eds.), The comprehensive sourcebook of bacterial protein toxins (4th ed.). New York: Academic.

    Google Scholar 

  • Scott, A. B., Rosenbaum, A., & Collins, C. C. (1973). Pharmacologic weakening of extraocular muscles. Invest Ophthalmol, 12, 924–7.

    CAS  PubMed  Google Scholar 

  • Shoemaker, C. B., & Oyler, G. A. (2013). Persistence of Botulinum neurotoxin inactivation of nerve function. Curr Top Microbiol Immunol, 364, 179–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Simpson, L. L. (2013). The life history of a botulinum toxin molecule. Toxicon, 68, 40–59.

    Article  CAS  PubMed  Google Scholar 

  • Smith, T. J., Hill, K. K., & Raphael, B. H. (2015). Historical and current perspectives on Clostridium botulinum diversity. Res Microbiol, 166, 290–302.

    Article  PubMed  Google Scholar 

  • Son, Y. J., & Thompson, W. J. (1995). Nerve sprouting in muscle is induced and guided by processes extended by Schwann cells. Neuron, 14, 133–41.

    Article  CAS  PubMed  Google Scholar 

  • Sun, S., Tepp, W. H., Johnson, E. A., & Chapman, E. R. (2012). Botulinum neurotoxins B and E translocate at different rates and exhibit divergent responses to GT1b and low pH. Biochemistry, 51, 5655–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sutton, R. B., Fasshauer, D., Jahn, R., & Brunger, A. T. (1998). Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature., 395, 347–53.

    Article  CAS  PubMed  Google Scholar 

  • Swaminathan, S., & Eswaramoorthy, S. (2000). Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B. Nat Struct Biol, 7, 693–9.

    Article  CAS  PubMed  Google Scholar 

  • Toivonen, J. M., Olivan, S., & Osta, R. (2010). Tetanus toxin C-fragment: the courier and the cure? Toxins (Basel), 2(11), 2622–44.

    Article  CAS  Google Scholar 

  • Umland, T. C., Wingert, L. M., Swaminathan, S., Furey, W. F., Schmidt, J. J., & Sax, M. (1997). Structure of the receptor binding fragment HC of tetanus neurotoxin. Nat Struct Biol, 4(10), 788–92.

    Article  CAS  PubMed  Google Scholar 

  • Vagin, O., Tokhtaeva, E., Garay, P. E., Souda, P., Bassilian, S., Whitelegge, J. P., Lewis, R., Sachs, G., Wheeler, L., Aoki, R., & Fernandez-Salas, E. (2014). Recruitment of septin cytoskeletal proteins by botulinum toxin A protease determines its remarkable stability. J Cell Sci, 127(Pt 15), 3294–308.

    Article  CAS  PubMed  Google Scholar 

  • Wheeler, A., & Smith, H. S. (2013). Botulinum toxins: mechanisms of action, antinociception and clinical applications. Toxicology, 306, 124–46.

    Article  CAS  PubMed  Google Scholar 

  • Whitemarsh, R. C., Tepp, W. H., Johnson, E. A., & Pellett, S. (2014). Persistence of botulinum neurotoxin A subtypes 1-5 in primary rat spinal cord cells. PLoS One, 9(2), e90252.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yeh, F. L., Dong, M., Yao, J., Tepp, W. H., Lin, G. Y., Johnson, E. A., et al. (2010). SV2 mediates entry of tetanus neurotoxin into central neurons. PLoS Pathog, 6, e1001207.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zanetti, G., Azarnia Tehran, D., Pirazzini, M., Binz, T., Shone, C. C., Fillo, S., Lista, F., Rossetto, O., & Montecucco, C. (2015). Inhibition of botulinum neurotoxins interchain disulfide bond reduction prevents the peripheral neuroparalysis of botulism. Biochem Pharmacol, 98, 522–30.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Work in the authors’ laboratory is supported by the University of Padova, Fondazione Cariparo, and the Italian Ministry of Defence.

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, University of Padova, Via Ugo Bassi n. 58/B, 35121, Padova, Italy

    Ornella Rossetto & Cesare Montecucco

  2. Consiglio Nazionale delle Ricerche, Institute of Neuroscience, University of Padova, Via Ugo Bassi n. 58/B, 35121, Padova, Italy

    Cesare Montecucco

Authors
  1. Ornella Rossetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cesare Montecucco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ornella Rossetto .

Editor information

Editors and Affiliations

  1. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    P. Gopalakrishnakone

  2. Biology Department, Wilson College , Chambersburg, Pennsylvania, USA

    Brad Stiles

  3. Department of Biochemistry, School of Medicine and Instituto Clodomiro Picado, Faculty of Microbiology, University of Costa Rica , San Pedro de Montes de Oca, Costa Rica

    Alberto Alape-Girón

  4. Département de pathologie et microbiologie, Faculté de médecine vétérinaire, Université de Montréal , Saint-Hyacinthe, Canada

    J. Daniel Dubreuil

  5. College of Pharmacy, Roseman University of Health Sciences, Henderson, Nevada, USA

    Manas Mandal

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Rossetto, O., Montecucco, C. (2016). Tetanus and Botulinum Neurotoxins. In: Gopalakrishnakone, P., Stiles, B., Alape-Girón, A., Dubreuil, J., Mandal, M. (eds) Microbial Toxins. Toxinology. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6725-6_19-1

Download citation

  • DOI: https://doi.org/10.1007/978-94-007-6725-6_19-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Dordrecht

  • Online ISBN: 978-94-007-6725-6

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation