title: Persistence of Botulinum neurotoxin inactivation of nerve function.
abstract: The extraordinary persistence of intoxication occurring after exposure to some Botulinum neurotoxin (BoNT) serotypes is both a therapeutic marvel and a biodefense nightmare. Understanding the mechanisms underlying BoNT persistence will offer new strategies for improving the efficacy and extending the applications of BoNT therapeutic agents as well as for treating the symptoms of botulism. Research indicates that the persistence of BoNT intoxication can be influenced both by the ability of the toxin protease or its cleaved soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein substrate to resist turnover. Protease turnover seems to be mediated in part by the ubiquitin-proteasome system (UPS) and efforts to manipulate the UPS may prove to be an effective strategy for improving therapeutic utility of BoNT products and in the development of botulism antidotes.
authors.affiliation: Division of Infectious Diseases, Department of Biomedical Sciences, Tufts Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA. charles.shoemaker@tufts.edu
authors.forename: Charles B
authors.initials: CB
authors.lastname: Shoemaker
authors.forename: George A
authors.initials: GA
authors.lastname: Oyler
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D001906:Botulism / Q000378:metabolism / Q000382:microbiology / Q000628:therapy; D003014:Clostridium botulinum / Q000472:pathogenicity; D004789:Enzyme Activation; D005089:Exocytosis; D006207:Half-Life; D006801:Humans; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010243:Paralysis / Q000378:metabolism / Q000382:microbiology / Q000628:therapy; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D050600:SNARE Proteins / Q000378:metabolism; D020539:Sequence Analysis, Protein; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D018675:Toxicity Tests; D054875:Ubiquitination
chemical_list: D009498:Neurotoxins; D011993:Recombinant Fusion Proteins; D050600:SNARE Proteins; D047992:TNF Receptor-Associated Factor 2; D010447:Peptide Hydrolases; D001905:Botulinum Toxins; D046988:Proteasome Endopeptidase Complex