Reactome: A Curated Pathway Database

Neurotoxicity of clostridium toxins (R-HSA-168799) [Homo sapiens]


Clostridial neurotoxins, when taken up by human neurons, block synaptic transmission by cleaving proteins required for the fusion of synaptic vesicles with the plasma membrane. They are remarkably efficient so that very small doses cause paralysis of an affected person (Lalli et al. 2003; Turton et al. 2002). All characterized clostridial neurotoxins are synthesized as products of chromosomal, plasmid or prophage-borne bacterial genes. The nascent toxin may be cleaved into light (LC) and heavy (HC) chain moieties that remain attached by noncovalent interactions and a disulfide bond (Turton et al. 2002).

Strains of Clostridium botulinum produce seven serologically distinct toxins, BoNT/A, B, C, D, E, F, and G. An eighth toxin, BoNT/H has recently been identified (Barash & Arnon 2014) but its molecular properties have not yet been described. Human poisoning most commonly result from ingestion of toxin contaminated food. More rarely, it is due to wound infection or clostridial colonization of the gut of an infant whose own gut flora have not yet developed or of an older individual whose flora have been suppressed. While all seven characterized toxins can cleave human target proteins, three, BoNT/A, B, and E, are most commonly associated with human disease (Hatheway 1995; Sakaguchi 1982). BoNT/F is also able to cause human botulism.

Once ingested, the botulinum toxin must be taken up from the gut lumen into the circulation, a process mediated by four accessory proteins. These proteins form a complex that mediates transcytosis of the toxin molecule across the gut epithelium, allowing its entry into the circulation. The accessory proteins produced by different C. botulinum strains differ in their affinities for polarized epithelia of different species (e.g., human versus canine), and may thus be a key factor in human susceptibility to the toxins of strains A, B, and E and resistance to the others (Simpson 2004).

Clostridium tetani produces TeNT toxin. Human poisoning is the result of toxin secretion by bacteria growing in an infected wound and the toxin is released directly into the circulation.

Circulating clostridial toxins are taken up by neurons at neuromuscular junctions. They bind to specific gangliosides (BoNT/C, TeNT) or to both gangliosides and synaptic vesicle proteins (BoNT/A, B, D G) exposed on the neuronal plasma membrane during vesicle exocytosis (Montal 2010). All seven characterized forms of BoNT are thought to be taken up into synaptic vesicles as these re-form at the neuromuscular junction. These vesicles remain close to the site of uptake and are rapidly re-loaded with neurotransmitter and acidified (Sudhoff 2004). TeNT, in contrast, is taken up into clathrin coated vesicles that reach the neuron cell body by retrograde transport and then possibly other neurons before undergoing acidification. Vesicle acidification causes a conformational change in the toxin, allowing its HC part to function as a channel through which its LC part is extruded into the neuronal cytosol. The HC - LC disulfide bond is cleaved and the cytosolic LC functions as a zinc metalloprotease to cleave specific bonds in proteins on the cytosolic faces of synaptic vesicles and plasma membranes that normally mediate exocytosis (Lalli et al. 2003; Montal 2010).

Name Identifier Synonyms
botulism 11976 [Botulism (disorder), Intoxication with Clostridium botulinum toxin, Botulism, Infection due to clostridium botulinum, Botulism, Foodborne botulism, botulism, Botulism, Botulism, Botulism, Food poisoning due to Clostridium botulinum, Botulism poisoning]
tetanus 11338 [clostridial tetanus, Tetanus (disorder), Infection due to Clostridium tetani (disorder)]
Literature References
pubMedId Title Journal Year
24106296 A Novel Strain of Clostridium botulinum That Produces Type B and Type H Botulinum Toxins J. Infect. Dis. 2014
8542759 Botulism: the present status of the disease Curr. Top. Microbiol. Immunol. 1995
13678859 The journey of tetanus and botulinum neurotoxins in neurons Trends Microbiol 2003
20233039 Botulinum neurotoxin: a marvel of protein design Annu. Rev. Biochem. 2010
6763707 Clostridium botulinum toxins Pharmacol. Ther. 1982
14744243 Identification of the major steps in botulinum toxin action Annu. Rev. Pharmacol. Toxicol. 2004
15217342 The synaptic vesicle cycle Annu Rev Neurosci 2004
12417130 Botulinum and tetanus neurotoxins: structure, function and therapeutic utility Trends Biochem Sci 2002