Botulinum neurotoxins (BoNTs) form a growing family of metalloproteases with a unique specificity either for VAMP, SNAP25 or syntaxin. The BoNTs are grouped in seven different serotypes indicated by letters from A to G. These neurotoxins enter the cytosol of nerve terminals via a 100 kDa chain which binds to the presynaptic membrane and assists the translocation of a 50 kDa metalloprotease chain. These two chains are linked by a single disulfide bridge which plays an essential role during the entry of the metalloprotease chain in the cytosol, but thereafter it has to be reduced to free the proteolytic activity. Its reduction is mediated by thioredoxin which is continuously regenerated by its reductase. Here we show that inhibitors of thioredoxin reductase or of thioredoxin prevent the specific proteolysis of VAMP by the four VAMP-specific BoNTs: type B, D, F and G. These compounds are effective not only in primary cultures of neurons, but also in preventing the in vivo mouse limb neuroparalysis. In addition, one of these inhibitors, Ebselen, largely protects mice from the death caused by a systemic injection. Together with recent results obtained with BoNTs specific for SNAP25 and syntaxin, the present data demonstrate the essential role of the thioredoxin-thioredoxin reductase system in reducing the interchain disulfide during the nerve intoxication mechanism of all serotypes. Therefore its inhibitors should be considered for a possible use to prevent botulism and for treating infant botulism.
|Number of pages||9|
|Publication status||Published - 1 Dec 2015|
Bibliographical noteFunding Information:
This work has been mainly supported by a grant from the Italian Ministry of Defence (Progetto PNRM—NIB, Segretariato Generale della Difesa V Reparto) and from Fondazione CARIPARO “Synaptic Functions and Role of Glial Cells in Brain and Muscle Diseases” to C.M., and additionally by a grant from the Ministero dell’Università e della Ricerca (Progetto PRIN) to O.R. We thank Editor and Reviewers for their comments and criticisms that led to an improved paper.
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- Botulinum neurotoxins
- Peripheral neuroparalysis
- Thioredoxin system