title: Anti-apoptotic activity of hemagglutinin-33 and botulinum neurotoxin and its implications to therapeutic and countermeasure issues.
abstract: Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum are the most toxic substances known to the mankind. BoNTs (seven serotypes, A-G) are produced along with a group of neurotoxin associated proteins (NAPs) in a physiologically coordinated manner, regulated by a common transcription factor for the gene cluster that encodes for the BoNT and NAPs. Hemagglutinin-33 (Hn-33) is a 33 kDa subcomponent of NAPs, which is resistant to protease digestion, and accounts for about half of the NAPs molecules in the BoNT/A complex. Natural exposures to BoNT in food poisoning cases as well as in the medical applications of BoNT as a therapeutic agent, humans are exposed to the BoNT/A complex. The toxin itself is known to block neurotransmitter release from presynaptic nerves, but the effect of NAPs is unexplored. In this article, we report an important observation of the anti-apoptotic effect of Hn-33 in Hn-33-preincubated human neuroblastoma SH-SY5Y cells. Activity of caspases, which are the central executioners of apoptosis, was substantially (78%) reduced by Hn-33. Degradation of chromosomal DNA, another biochemical hallmark of apoptosis, was blocked in Hn-33 incubated SH-SY5Y cells. Interestingly, purified BoNT/A also showed substantial anti-apoptotic activity. These findings may have significant implications to the use of BoNT as a therapeutic agent, and to devise counter measures to botulinum poisoning.
authors.affiliation: Department of Chemistry and Biochemistry, The Botulinum Research Center, University of Massachusetts Dartmouth, North Dartmouth, MA 02747, United States.
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Koyel
authors.initials: K
authors.lastname: Ghosal
authors.forename: Shuowei
authors.initials: S
authors.lastname: Cai
authors.forename: Bal Ram
authors.initials: BR
authors.lastname: Singh
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001905:Botulinum Toxins / Q000494:pharmacology* / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans
chemical_list: C118973:hemagglutinin 33 protein, Clostridium botulinum; D020169:Caspases; D001905:Botulinum Toxins