Thioredoxin and its reductase are present on synaptic vesicles, and their inhibition prevents the paralysis induced by botulinum neurotoxins

Marco Pirazzini, Domenico Azarnia Tehran, Giulia Zanetti, Aram Megighian, Michele Scorzeto, Silvia Fillo, Clifford Shone, Thomas Binz, Ornella Rossetto, Florigio Lista, Cesare Montecucco*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

Abstract

Botulinum neurotoxins consist of a metalloprotease linked via a conserved interchain disulfide bond to a heavy chain responsible for neurospecific binding and translocation of the enzymatic domain in the nerve terminal cytosol. The metalloprotease activity is enabled upon disulfide reduction and causes neuroparalysis by cleaving the SNARE proteins. Here, we show that the thioredoxin reductase-thioredoxin protein disulfide-reducing system is present on synaptic vesicles and that it is functional and responsible for the reduction of the interchain disulfide of botulinum neurotoxin serotypes A, C, and E. Specific inhibitors of thioredoxin reductase or thioredoxin prevent intoxication of cultured neurons in a dose-dependent manner and are also very effective inhibitors of the paralysis of the neuromuscular junction. We found that this group of inhibitors of botulinum neurotoxins is very effective invivo. Most of them are nontoxic and are good candidates as preventive and therapeutic drugs for human botulism.

Original languageEnglish
Pages (from-to)1870-1878
Number of pages9
JournalCell Reports
Volume8
Issue number6
DOIs
Publication statusPublished - 25 Sep 2014

Bibliographical note

Funding Information:
We thank Valentina Pittiglio and Francesco Giordani for valuable technical assistance. This work was supported by the Italian Ministry of Defence (Progetto PNRM - NIB, Segretariato Generale della Difesa V Reparto), Fondazione CARIPARO “Synaptic Functions and Role of Glial Cells in Brain and Muscle Diseases” (to C.M.), and a grant from the Ministero dell’Università e della Ricerca (Progetto PRIN) to O.R.

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