Abstract
Botulism, Clostridia and Botulinum Neurotoxins
Botulism is a paralysis of peripheral cholinergic nerve terminals caused in vertebrate animals by botulinum neurotoxins (BoNTs), which are produced by anaerobic bacteria of the genus Clostridium. These are the most poisonous substances known to humans and are included in the list A of potential bioterrorist weapons. At the same time they have become, thanks to scientific and clinical research, therapeutics used in millions of doses in humans. Traditionally seven serotypes were known, but recent genomics has already characterized > 40 different BoNTs posing the problem of the reasons behind the evolution of so many botulinum neurotoxins. Great advances on their structure and of those the peculiar BoNT-nerve receptors complexes have been recently made and will be discussed as well as their elaborate mode of entry into nerve terminals. This involves the translocation of a 50 kDa metalloprotease domain from the lumen of an endocytic synaptic vesicle across the membrane into the cytosol, where it cleaves any of the three SNARE proteins. The SNAREs are the core of the nanomachine which mediates the Ca2+-controlled release of neurotransmitters at the synapse. We recently found that a key step for the display of the toxin metalloprotease activity is the reduction of a single disulphide bond operated by a a thioredoxin reductase-thioredoxin system associated to synaptic vesicles. Consequently we identified a group of molecules that inhibit this redox system and prevent reduction and paralysis in vivo. Finally, I will discuss a model for the entry of BoNTs into neurons that explains the presently available data and provides the frame for the future molecular understanding of this process.
Biography
Born in Trento (Italy), Cesare is currently Professor of General Pathology at the University of Padova where he coordinates the Laboratory of Neurotoxins, Neuroparalysis and Regeneration. He has also carried out research in the Universities of Cambridge, Utrecht, and Costa Rica, the Institut Pasteur of Paris and the EMBL of Heidelberg.
He has studied the molecular and cellular pathogenesis of diseases caused by toxin producing pathogenic bacteria (anthrax, botulism, tetanus, Helicobacter pylori) and by poisonous snakes and insects. A major discovery was the identification of proteins that compose the nanomachine that mediates the release of neurotransmitters and hormones.
For present research, please see: (http://www.biomed.unipd.it/research/neurotoxins-neuroparalysis-and-regeneration/overview/). He is member of several scientific academies has received several scientific prizes, including the Feltrinelli Prize for Medicine 2004, the Redi Award 2009 and the Ehrlich Prize for Medicine 2011.