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The Mechanism of Action of Tetanus and Botulinum Neurotoxins

  • Conference paper
Toxicology - From Cells to Man

Part of the book series: Archives of Toxicology ((TOXICOLOGY,volume 18))

Abstract

Tetanus and botulinum neurotoxins were identified about a century ago as the cause of the neuroparalytic syndromes of tetanus and botulism (Faber, 1890; Tizzoni & Cattani, 1890; van Ermengem, 1897). Bacteria of the genus Clostridium produce one tetanus neurotoxin (TeNT) and seven different serotypes of botulinum neurotoxins (BoNT/A, /B, /C, /D, /E, /F, and /G). These bacteria show a widespread distribution in the environment, mainly as spores, which can germinate under appropriate anaerobic conditions. Tetanus follows the contamination of necrotic wounds with spores of Clostridium tetani, limited bacterial proliferation and toxin production. Botulism derives from ingestion of uncooked anaerobic food, where spores of Clostridium botulinum, or related species, have germinated with the production of the toxin (foodborne botulism). More rarely, spores germinate in anaerobic areas of the newborn intestine giving rise to infant botulism (Simpson, 1989; Montecucco, 1995). Since tetanus is caused solely by intoxication with TeNT, it was possible to prepare a anti-tetanus vaccine simply by treating TeNT with paraformaldheyde, a chemical modification that inactivates the toxin, but preserves its immunogenic properties (Ramon & Descombey, 1925).

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References

  • Bennett, M.K., Calakos, N. & Scheller, RH. (1992) Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science, 257, 255–259.

    Article  PubMed  CAS  Google Scholar 

  • Bennett, M.K. & Scheller, R.H. (1994) A molecular description of synaptic vesicle membrane trafficking. Annu. Rev. Biochem. 63, 63–100.

    Article  CAS  Google Scholar 

  • Beise, J., Hahnen, J., Andersen-Beckh, B. & Dreyer, F. (1994) Pore formation by tetanus toxin, its chain and fragments in neuronal membranes and evaluation of the underlying motifs in the structure of the toxin molecule. Naunyn-Schmiedeberg’s Arch. Pharmacol., 349, 66–73.

    CAS  Google Scholar 

  • Binz, T., Blasi, J., Yamasaki, S., Baumeister, A., Link, E., Südhof, T.C., Jahn, R. & Niemann, H. (1994) Proteolysis of SNAP-25 by types E and A botulinal neurotoxins. J. Biol. Chem., 269, 1617–1620.

    CAS  Google Scholar 

  • Blasi, J., Chapman, E.R, Link, E., Binz, T., Yamasaki, S., De Camilli, P., Südhof, T., Niemann, H. & Jahn, R. (1993) Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature, 365, 160–163.

    Article  PubMed  CAS  Google Scholar 

  • Blasi, J., Chapman, E.R, Yamasaki, S., Binz, T., Niemann, H. & Jahn, R. (1993) Botulinum neurotoxin C blocks neurotransmitter release by means of cleaving HPC- 1/syntaxin. EMBO J., 12, 4821–4828.

    PubMed  CAS  Google Scholar 

  • Blaustein, R.O., Germann, W.J., Finkelstein, A. & DasGupta, B.R (1989) The N-terminal half of the heavy chain of botulinum type A neurotoxin forms channels in planar phospholipid bilayers. FEBS Lett., 226, 115–120.

    Article  Google Scholar 

  • Boquet, P. & Duflot, E. (1982) Tetanus toxin fragment forms channels in lipid vesicles at low pH. Proc. Natl. Acad. Sci. USA, 79, 7614–7618.

    Article  PubMed  CAS  Google Scholar 

  • Burgen, A.S.V., Dickens, F. & Zatman, L.Y. (1949) The action of botulinum toxin on the neuromuscular junction. J. Physiol. (London), 109, 10–24.

    CAS  Google Scholar 

  • de Paiva, A., Poulain, B., Lawrence, G.W., Shone, C.C., Tauc, L. & Dolly, J O. (1993) A role for the interchain disulfide or its participating thiols in the internalization of botulinum neurotoxin A revealed by a toxin derivative that bindl to ecto-acceptors and inhibits transmitter release intracellularly. J. Biol. Chem., 268, 20838–20844.

    PubMed  Google Scholar 

  • Dayanithi, G., Stecher, B., Hohne-Zell, B., Yamasaki, S., Binz, T., Weller, U., Niemann, H. & Gratzl, M. (1994) Exploring the functional domain and the target of the tetanus toxin light chain in neurohypophysial terminals. Neuroscience, 58, 423–431.

    Article  PubMed  CAS  Google Scholar 

  • Donovan, J.J. & Middlebrook, J.L. (1986) Ion-conducting channels produced by botulinum toxin in planar lipid membranes. Biochemistry, 25, 2872–2876.

    Article  PubMed  CAS  Google Scholar 

  • Faber, K. (1890) Die Pathogenie des Tetanus. Berl. klin. Wochenschr., 27, 717–720.

    Google Scholar 

  • Gambale, F. & Montal, M. (1988) Characterization of the channel properties of tetanus toxin in planar lipid bilayers. Biophys. J., 53, 771–783.

    Article  PubMed  CAS  Google Scholar 

  • Hayashi, T., McMahon, H., Yamasaki, S., Binz, T., Hata, Y., Sudhof, T.C. & Niemann, H. (1994) Synaptic vesicles membrane fusion complex: action of clostridial neurotoxins on assembly. EMBO J. 13, 5051–5061.

    PubMed  CAS  Google Scholar 

  • Hoch, D.H., Romero-Mira, M., Ehrlich, B.E., Finkelstein, A., DasGupta, B.R. & Simpson, L.L. (1985) Channels formed by botulinum, tetanus, and diphtheria toxins in planar lipid bilayers: relevance to translocation of proteins across membranes. Proc. Natl. Acad. Sci. USA, 82, 1692–1696.

    Article  PubMed  CAS  Google Scholar 

  • Hohne-Zell, B., Stecher, B. & Gratzl, M. (1993) Functional characterization of the catalytic site of the tetanus toxin light chain using permeabilized adrenal chromaffin cells. FEBS Lett., 336, 175–180.

    Article  PubMed  CAS  Google Scholar 

  • Kurazono, H., Mochida, S., Binz, T., Eisel, U., Quanz, M., Grebenstein, O., Wernars, K., Poulain, B., Tauc, L. & Niemann, H. (1992) Minimal essential domains specifying toxicity of the light chains of tetanus toxin and botulinum nurotoxin type A. J. Biol. Chem. 267, 14721–14729.

    PubMed  CAS  Google Scholar 

  • Inoue, A., Obata, K. & Akagawa, K. (1992) Cloning and sequence analysis of cDNA for a neuronal cell membrane antigen, HPC-1. J. Biol. Chem., 267, 10613–10619.

    PubMed  CAS  Google Scholar 

  • Jankovic, J. & Hallett, M. (eds.) (1994) Therapy with botulinum toxin. Marcel Dekker, New York.

    Google Scholar 

  • Matteoli, M., Takei, K., Perin, M.S., Sudhof, T.C. & De Camilli, P. (1992) Exo- endocytotic recycling of synaptic vesicles in developing processes of cultured hippocampal neurons. J. Cell. Biol., 117, 849–861.

    Article  PubMed  CAS  Google Scholar 

  • Matthews, B.W., Jansonius, J.N. & Colman, P.M. (1972) Three-dimensional structure of thermolysin. Nature New. Biol., 238, 37–41.

    Article  PubMed  CAS  Google Scholar 

  • McMahon, H.T., Ushkaryov, Y.A., Edelmann, L., Link, E., Binz, T., Niemann, H., Jahn, R. & Sudhof, T.C. (1993) Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein. Nature, 364, 346–349.

    Article  PubMed  CAS  Google Scholar 

  • Menestrina, G., Forti, S. & Gambale, F. (1989) Interaction of tetanus toxin with lipid vesicles: effects of pH, surface charge, and transmembrane potential on the kinetics of channel formation. Biophys. J., 55, 393–405.

    Article  PubMed  CAS  Google Scholar 

  • Minton, N. (1995) Molecular genetics of clostridial neurotoxins. In Clostridial Neurotoxins (ed. C. Montecucco ), Curr. Top. Microbiol. Immunol, vol. 195.

    Google Scholar 

  • Montecucco, C. (1986) How do tetanus and botulinum toxins bind to neuronal membranes? Trends Biochem. Sci., 11, 314–317.

    Article  CAS  Google Scholar 

  • Montecucco, C. (1986) How do tetanus and botulinum toxins bind to neuronal membranes? Trends Biochem. Sci., 11, 314–317.

    Article  CAS  Google Scholar 

  • Montecucco, C., Schiavo, G., Brunner, J., Duflot, E, Boquet, P. & Roa, M. (1986) Tetanus toxin is labeled with photoactivatable phospholipids at low pH. Biochemistry 25, 919–924.

    Article  PubMed  CAS  Google Scholar 

  • Montecucco, C., Schiavo, G., Gao, Z., Bauerlein, E., Boquet, P. & DasGupta, B.R. (1988). Interaction of botulinum and tetanus toxins with the lipid bilayer surface. Biochem. J., 259, 47–53.

    Google Scholar 

  • Montecucco, C., Schiavo, G. & DasGupta, B.R. (1989). Effect of pH on the interaction of botulinum neurotoxins A, B and E with liposomes. Biochem. J., 259, 47–53.

    CAS  Google Scholar 

  • Montecucco, C. & Schiavo, G. (1993) Tetanus and botulism neurotoxins: a new group of zinc proteases. Trends Biochem. Sci. 18, 324–327.

    CAS  Google Scholar 

  • Montecucco, C. & Schiavo, G. (1993) Tetanus and botulism neurotoxins: a new group of zinc proteases. Trends Biochem. Sci. 18, 324–327.

    CAS  Google Scholar 

  • Montecucco, C., Papini, E. & Schiavo, G. (1994) Bacterial protein toxins penetrate cells via a four-step mechanism. FEBS Lett. 346, 92–98.

    Article  PubMed  CAS  Google Scholar 

  • Osen-Sand, A., Catsicas, M., Staple, J.K., Jones, K.A., Ayala, G., Knowles, J., Grenningloh, G. & Catsicas, S. (1993) Inhibition of axonal growth by SNAP-25 antisense oligonucleotides in vitro and in vivo. Nature, 364, 445–448.

    Article  PubMed  CAS  Google Scholar 

  • Oyler, G.A., Higgins, G.A., Hart, R.A., Battenberg, E, Billingsley, M., Bloom, F.E. & Wilson, M.C. (1989) The identification of a novel synaptosomal-associated protein, SNAP-25, differently expressed by neuronal subpopulations. J. Cell. Biol. 109, 3039–3052.

    Article  PubMed  CAS  Google Scholar 

  • Patarnello, T., Bargelloni, L., Rossetto, O., Schiavo, G. & Montecucco, C. (1993) Neurotransmission and secretion. Nature, 364, 581–582.

    Article  PubMed  CAS  Google Scholar 

  • Payling-Wright, G. (1955) The neurotoxins of Clostridium botulinum and Clostridum tetani. Pharmacol. Rev., 7, 413–465.

    Google Scholar 

  • Ramon, G. & Descombey, P. A. (1925) Sur rimmunization antitetanique et sur la production de l’antitoxine tetanique. Compt. Rend. Soc. Biol., 93, 508–598.

    CAS  Google Scholar 

  • Roa, M. & Boquet, P. (1985) Interaction of tetanus toxin with lipid vescicles at lowpH. J. Biol. Chem., 260, 6827–6835.

    PubMed  CAS  Google Scholar 

  • Rossetto, O., Schiavo, G. Montecucco, C., Poulain, B., Deloye, F., Lozzi, L. & Shone, C.C. (1994) SNARE motif and neurotoxin recognition. Nature 372, 415–416.

    Article  PubMed  CAS  Google Scholar 

  • Schiavo, G., Papini, E., Genna, G. & Montecucco, C. (1990) An intact interchain disulfide bond is required for the neurotoxicity of tetanus toxin. Infect. Immun., 58, 4136–4141.

    PubMed  CAS  Google Scholar 

  • Schiavo, G., Demel, R. & Montecucco, C. (1991a) On the role of polysialoglycosphingolipids as tetanus toxin receptors: a study with lipid monolayers. Eur. J. Biochem. 199, 705–711.

    Article  CAS  Google Scholar 

  • Schiavo, G., Rossetto, O., Ferrari, G. & Montecucco, C. (1991b) Tetanus toxin receptor. Specific cross-linking of tetanus toxin to a protein of NGF-differentiated PC 12 cells. FEBS Lett., 290, 227–230.

    Article  CAS  Google Scholar 

  • Schiavo, G., Poulain, B., Rossetto, O., Benfenati, F., Tauc, L. & Montecucco, C. (1992a) Tetanus toxin is a zinc protein and its inhibition of neurotrasmitter release and protease activity depend on zinc. EMBO J., 11, 3577–3583.

    CAS  Google Scholar 

  • Schiavo, G., Benfenati, F., Poulain, B., Rossetto, O., Polverino de Laureto, P., DasGupta, B.R. & Montecucco, C. (1992b) Tetanus and botulinum-B neurotoxins block neurotransmitter release by a proteolytic cleavage of synaptobrevin. Nature, 359, 832–835.

    Article  CAS  Google Scholar 

  • Schiavo, G., Rossetto, O., Santucci, A., DasGupta, B.R. & Montecucco, C. (1992c) Botulinum neurotoxins are zinc proteins. J. Biol. Chem., 267, 23479–23483.

    CAS  Google Scholar 

  • Schiavo, G., Shone, C.C., Rossetto, O., Alexandre, F.C.G. & Montecucco, C. (1993a) Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synaptobrevin. J. Biol. Chem., 268, 11516–11519.

    CAS  Google Scholar 

  • Schiavo, G., Rossetto, O., Catsicas, S., Polverino de Laureto, P., DasGupta, B.R., Benfenati, F. & Montecucco, C. (1993b) Identification of the nerve-terminal targets of botulinum neurotoxins serotypes A, D and E. J. Biol. Chem., 268, 23784–23787.

    CAS  Google Scholar 

  • Schiavo, G., Santucci, A., DasGupta, B.R., Methav, P.P., Jontes, J., Benfenati, F., Wilson, M.C. & Montecucco, C. (1993c) Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. FEBS Lett., 335, 99–103.

    CAS  Google Scholar 

  • Schiavo, G., Malizio, C., Trimble, W.S., Polverino de Laureto, P., Milan, G., Sugiyama, H., Johnson, E.A. & Montecucco, C. (1994). Botulinum G neurotoxin cleaves VAMP/synaptobrevin at a single Ala/Ala peptide bond. J. Biol. Chem. 269, 20213–20216.

    Google Scholar 

  • Schiavo, G., Shone, C.C., Bennett, M.K., Scheller, R.H. & Montecucco, C. (1995) Botulinum neurotoxin type C cleaves a single Lys-Ala bond within the carboxyl- terminal region of syntaxins. J. Biol. Chem., 270, 10566–10570.

    Article  PubMed  CAS  Google Scholar 

  • Schwab, M.E., Suda, K. & Thoenen, H. (1979) Selective retrograde trans-synaptic transfer of a protein, tetanus toxin, subsequent to its retrograde axonal transport. J. Cell. Biol., 82, 798–810.

    Article  PubMed  CAS  Google Scholar 

  • Simpson, L.L. (1989) (ed) Botulinum neurotoxins and tetanus toxin. Academic Press, New York.

    Google Scholar 

  • Simpson, L.L., Coffield, J.A. & Bakry, N. (1994) Inhibiton of vacuolar adenosine triphosphatase antagonizes the effects of clostridial neurotoxins but not phospholipase A2 neurotoxins. J. Pharmacol. Exp. Ther. 269, 256–262.

    PubMed  CAS  Google Scholar 

  • Shone, C.C., Hambleton, P. & Melling, J. (1987) A 50 kDa fragment from the N-terminus of the heavy subunit of Clostridium botulinum type A neurotoxin forms channels in lipid vesicles. Eur. J. Biochem., 167, 175–180.

    Article  PubMed  CAS  Google Scholar 

  • Shone, C.C., Quinn, CP., Wait, R, Hallis, B., Fooks, S.G. & Hambleton, P. (1993) Proteolytic cleavage of synthetic fragments of vesicle-associated membrane protein, isoform-2 by botulinum type B neurotoxin. Eur. J. Biochem. 217, 965–971.

    Article  PubMed  CAS  Google Scholar 

  • Shone, C.C. & Roberts, A.K. (1994) Peptide substrate specificity and properties of the zinc-endopeptidase activity of botulinum type B neurotoxin. Eur. J. Biochem. 225, 263–270.

    Article  PubMed  CAS  Google Scholar 

  • Sollner, T., Whiteheart, S.W., Brunner, M., Erdjument-Bromage, H., Geromanos, S., Tempst, P. & Rothman, J.E. (1993) SNAP receptors implicated in vesicle targeting and fusion. Nature 362, 318–324.

    Article  PubMed  CAS  Google Scholar 

  • Stocker, W., Grams, F., Baumann, U., Reinemer, P., Gomis-Ruth, F X., McKay, D.B. & Bode, W. (1995) The metzincins-Topological and sequential relations between the astacins, adamalysins, serralysins and matrixins (collagenases) define a superfamily of zinc-peptidases. Protein Science 4, 823–840.

    Article  PubMed  CAS  Google Scholar 

  • Südhof, T.C. (1995) The synaptic vesicle cycle: a cascade of protein protein interactions. Nature, 375, 645–653.

    Article  PubMed  Google Scholar 

  • Sweeney, S.T., Broadie, K., Keane, J., Niemann, H. & O’Kane, J. (1995) Targeted expression of tetanus toxin light chain in Drosophila specifically eliminates synaptic transmission and causes behavioural defects. Neuron 14, 341–351.

    Article  PubMed  CAS  Google Scholar 

  • Tizzoni, G. & Cattani, G. (1890) Untersuchungen iiber das Tetanusgift. Arch. exp. Pathol. Pharmakol. 27, 432–450.

    Google Scholar 

  • van Ermengem, E. (1897) šber einem neuen anaeroben Bacillus und seine Beziehungen zum Botulismus. Z. Hyg. InfektKr. 26, 1–56.

    Article  Google Scholar 

  • Yamasaki, S., Baumeister, A, Binz, T., Blasi, J., Link, E., Cornille, F., Roques, B., Fykse, E.M., Südhof, T.C., Jahn, R. & Niemann, H. (1994b) Cleavage of members of the synaptobrevin/VAMP family by types D and F botulinal neurotoxins and tetanus toxin. J. Biol. Chem. 269, 12764–12772.

    CAS  Google Scholar 

  • Wellhoner, H.H. (1992) Tetanus and botulinum neurotoxins. In Handbook of Experimental Pharmacology, vol. 102 (eds H. Herken & F. Hucho), Springer-Verlag, Berlin, pp. 357–417. Williamson, L.C. & Neale, E.A. (1994) Bafilomycin A1 inhibits the action of tetanus toxin in spinal cord neurons in cell culture. J. Nerochem. 63, 2342–2345.

    Google Scholar 

  • Wright, J.F., Pernollet, M., Reboul, A., Aude, C. & Colomb, M. (1992) Identification and partial characterization of a low affinity metal-binding site in the light chain of tetanus toxin. J. Biol. Chem., 267, 9053–9058.

    PubMed  CAS  Google Scholar 

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  1. Centro CNR Biomembrane, Dipartimento di Scienze Biomediche, Universitá di Padova, 35100, Padova, Italy

    Cesare Montecucco, Giampietro Schiavo & Ornella Rossetto

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  1. Cesare Montecucco
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  2. Giampietro Schiavo
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  3. Ornella Rossetto
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  1. Interkantonale Kontrollstelle für Heilmittel, Erlachstrasse 8, CH-3000, Bern 9, Switzerland

    Jürg P. Seiler

  2. Department of Pharmacology, Charles University of Prague, 3rd Medical School, Ruská 87, Czech Republic

    Olga Kroftová

  3. Department of Pharmacology, Charles University, Faculty of Medicine, Karlovarská 48, CZ-30166, Pilsen, Czech Republic

    Vladislav Eybl

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Montecucco, C., Schiavo, G., Rossetto, O. (1996). The Mechanism of Action of Tetanus and Botulinum Neurotoxins. In: Seiler, J.P., Kroftová, O., Eybl, V. (eds) Toxicology - From Cells to Man. Archives of Toxicology, vol 18. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-61105-6_32

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