Botulism is characterized by flaccid paralysis, which can be caused by intoxication with any of the seven known serotypes of botulinum neurotoxin (BoNT). BoNT serotype A (BoNT/A) has the most prolonged symptoms due to an extraordinarily stable catalytic light chain (LCA).
The botulism neurotoxin BoNT/A blocks neurotransmission by cleaving the SNARE protein SNAP25, resulting in paralysis that can last 2–6 months.
Researchers report that a deubiquitinating enzyme (DUB) accounts for the prolonged duration of BoNT/A paralysis and might be targeted to mitigate the toxin’s effect. BoNT/A, the authors report, inactivates SNAP25 once it binds to specific receptors on neurons and delivers the catalytic light chain protease into cells.
Typically, cells flag foreign proteins for destruction by marking them with ubiquitin through the action of ubiquitin ligase enzymes. However, the BoNT/A light chain remains enzymatically active for months after entering cells.
The authors report that the stability reflects the action of the DUB, VCIP135/VCPIP1, which binds the BoNT/A light chain directly, removes ubiquitin, and allows the toxin to evade degradation by the proteasome.
Loss of VCIP135 in neurons compromised by BoNT/A promotes the recovery of SNAP25 with no observable toxicity, according to the authors.\
http://www.pnas.org/content/early/2017/05/31/1621076114
Mechanism of botulinum mediated long term paralysis
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