Botulinum toxins are currently used on more than 80 medical conditions including Muscle spasms, Overactive bladder, Chronic migraine, Cervical dystonia, Sweating and Cerebral Palsy (CP). The new toxin, Botulinum neurotoxin type X (BoNT/X), has the potential to open up a new field of toxin therapeutics related to intracellular membrane trafficking and secretion.
It all started with an infant in Japan that became ill in 1995. In 2015 the genome of the bacteria isolated from the child was sequenced and deposited in a database. Hidden in the four million letter blueprint of the bacterium, the research team identified the novel toxin.
BoNT/X has the lowest sequence identity with other BoNTs and is not recognized by antisera against known BoNTs. Similar to BoNT/B/D/F/G, BoNT/X cleaves vesicle-associated membrane proteins (VAMP) 1, 2 and 3, but at a novel site (Arg66-Ala67 in VAMP2).
Remarkably, BoNT/X is the only toxin that also cleaves non-canonical substrates VAMP4, VAMP5 and Ykt6. To validate its activity, a small amount of full-length BoNT/X was assembled by linking two non-toxic fragments using a transpeptidase (sortase). Assembled BoNT/X cleaves VAMP2 and VAMP4 in cultured neurons and causes flaccid paralysis in mice. Thus, BoNT/X is a novel BoNT with a unique substrate profile.
"When we first discovered this toxin I believed we had made some error in the analysis, but after checking several times it turned out to be correct.
Since Botulinum neurotoxins are the most toxic substances known, the development of detection methods and treatments is very important.
"The discovery of BoNT/X facilitates the development of diagnostics and counter measures which is important if someone would be exposed to a toxic amount of the substance", says corresponding author.
The research team will now develop antibodies with the ability to detect and inactivate the toxin.
The researchers will determine the structure of the toxin and investigate how it binds to the nerve cell. They will also investigate how the unique properties of BoNT/X can be best used to develop new therapeutics.
New botulinum neurotoxin discovered!
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