The thioredoxin reductase - Thioredoxin redox system cleaves the interchain disulphide bond of botulinum neurotoxins on the cytosolic surface of synaptic vesicles

Marco Pirazzini*, Domenico Azarnia Tehran, Giulia Zanetti, Florigio Lista, Thomas Binz, Clifford Shone, Ornella Rossetto, Cesare Montecucco

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    24 Citations (Scopus)

    Abstract

    Botulinum neurotoxins (BoNTs) are Janus toxins, as they are at the same time the most deadly substances known and one of the safest drugs used in human therapy. They specifically block neurotransmission at peripheral nerves through the proteolysis of SNARE proteins, i.e. the essential proteins which are the core of the neuroexocytosis machinery. Even if BoNTs are traditionally known as seven main serotypes, their actual number is much higher as each serotype exists in many different subtypes, with individual biological properties and little antigenic relations. Since BoNTs can be used as biological weapons, and the only currently available therapy is based on immunological approaches, the existence of so many different subtypes is a major safety problem. Nevertheless, all BoNT isoforms are structurally similar and intoxicate peripheral nerve endings via a conserved mechanism. They consist of two chains linked by a unique disulphide bond which must be reduced to enable their toxicity. We found that thioredoxin 1 and its reductase compose the cell redox system responsible for this reduction, and its inhibition via specific chemicals significantly reduces BoNTs activity, in vitro as well as in vivo. Such molecules can be considered as lead compounds for the development of pan-inhibitors.

    Original languageEnglish
    Pages (from-to)32-36
    Number of pages5
    JournalToxicon
    Volume107
    DOIs
    Publication statusPublished - 1 Dec 2015

    Bibliographical note

    Publisher Copyright:
    © 2015 Elsevier Ltd. All rights reserved.

    Keywords

    • Botulinum neurotoxins
    • Inhibitors
    • Synaptic vesicles
    • Thioredoxin
    • Thioredoxin reductase

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