MECHANISM OF ACTION OF BOTULINUM NEUROTOXIN

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DESCRIPTION (from applicant's abstract): While botulinum neurotoxin (BTx) is the most poisonous biological toxin identified so far, it has proven to be a useful therapeutic agent for the treatment of various focal dystonias. Recently, the mechanism by which BTx inhibits neurotransmitter release was shown to be by its proteolytic action on a protein needed for the "docking" of synaptic vesicles. There are however, many unanswered fundamental questions about the mechanism of action of BTx. The overall objective of this proposal is to further define its adherence to cells and its in vivo effect on its synaptosomal protein substrate. This will be accomplished by determining 1) the number and identity of clustered ganglioside-oligosaccharide residues needed for its optimum adherence, 2) the precise region of the carboxy-terminal half of the heavy chain needed for its adherence to gangliosides, 3) whether the ganglioside binding site is the only site needed for its cell adherence, and 4) the half-life of BTxA and BTxE in vivo, as well as their effect on the level of SNAP-25 protein (SNAP-25 is the docking component acted upon by these two serotypes of BTx). Answers to these questions may explain the long-lasting effects induced by BTx, result in its more effective clinical use, and suggest a possible alternative to the use of antiserum for the treatment of individuals that come into contact with Clostridium botulinum or its neurotoxin.