Botulinum neurotoxicity Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 Botulism, caused by botulinum neurotoxin (BoNT), is characterized by descending flaccid paralysis as a result of inhibition of neurotransmitter release at the neuromuscular junction - NMJ (Turton et al., 2002). According to their antigenic properties, BoNTs are classified into seven different toxin types (A, B, C1, D, E, F and G) although more than 50 sequences encoding 18 subtypes are known (Smith et al., 2005). The toxin is released as a 900 kDa complex containing some accessory proteins of unknown functions (Chen et al., 1998). The toxin types A, B and E are mainly involved in human botulism whereas C and D predominantly cause animal botulism (Poulain et al, 2006). The toxin is absorbed from the gut or other epithelium and reaches neuromuscular junctions by transcytosis (Park and Simpson, 2003). The binding sites for the toxins are distributed across the apical surface of the epithelium (Ahsan et al., 2005). It has been observed that the neurotoxin alone is capable of transcytosis across epithelial cells (Maksymowych and Simpson, 2004). Once internalized, the neurotoxin is dissociated from the non-toxic components of the progenitor toxin in endosome (Uotsu et al., 2006). <br> The neurological inhibition is caused by the specific cleavage of a group of proteins integral to NMJ exocytosis, SNARE proteins (soluble NSF-attachment protein receptors). One or more SNARE proteins are cleaved by BoNT, blocking the release of synaptic vesicular contents like acetylcholine as in the case of motor neurons. <br>BoNTs are synthesized as polypeptides of 150 kDa that are cleaved into heavy and light chains linked by a single disulfide bond. Cleavage takes place within a surface-exposed loop at the N-terminal of the Heavy chain subunit. Both bacterial and host endopeptidases can catalyze BoNT cleavage into heavy and light chains, but bacterial enzymes are thought to carry out this function in vivo.The Heavy Chain (HC) has two 50 kDa functional domains: the N-terminal translocation domain is capable of forming channels in lipid bilayers; the C-terminal ganglioside-binding domain is important for membrane binding and subsequent internalization of toxins by host neurons. The 50 kDa Light chain (LC) is a zinc-dependent endopeptidase specific for core components of neurotransmitter release complexes.<br>BoNT action proceeds in the following steps: binding of cleaved toxin to the target cell membrane; transcytosis from epithelial membrane to target neuromuscular junction cells; release of BoNT Light chain into the target cell cytosol; and proteolytic cleavage of target cell proteins catalyzed by the BoNT Light chain.<br> Edited: Gopinathrao, G, 2006-06-15 22:12:29 GENE ONTOLOGYGO:0007269 Neurotoxicity of Botulinum toxins Pubmed12417130 Pubmed12595426 Pubmed15140915 Pubmed16113261 Pubmed16144978 Pubmed16413070 Pubmed7527117 Pubmed9596697 Reactome Database ID Release 43168799 Reactome, http://www.reactome.org ReactomeREACT_11184 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 Proteolytic cleavage of SNARE complex proteins Translocation of BoNT Light chain PathwayStep3433 PathwayStep3419 PathwayStep3418 PathwayStep3423 Transcytosis and internalization of BoNT Binding of BoNT toxins to gut epithelial membrane