Molecular Basis for Persistence of Botulinum Neurotoxin: The Role of Intracellular Protein Degradation Pathways
A key aspect of botulinum neurotoxin biology, which underpins both the nature of botulism and the clinical success of therapeutic neurotoxin preparations, is the duration of effect of the neurotoxin on neurotransmitter release. There are seven different distinct serotypes of botulinum neurotoxins which exhibit a wide range in the duration of action or “persistence” after intoxications. The biological basis of persistence is beginning to be understood. One mechanism which underpins the duration of neurotoxin activity is survival of the light chain within the presynaptic terminal of the intoxicated neuron. For the neurotoxin light chain to remain in the presynaptic terminal maintaining the intoxication state, the bacterial protein must evade the two major pathways for cellular protein degradation, the ubiquitin–proteasome system degradation and the lysosomal/autophagy mechanism. A role for substrate cleavage products in persistence has also been suggested in perpetuating the intoxication state. These various ideas and the evidence for and against them are reviewed. The opportunity to modify the persistence of the neurotoxin and its therapeutic potential is also considered.
KeywordsBioterrorism Botulinum neurotoxin Ubiquitination Deubiquitination Persistence
This research was supported in part by the Defense Threat Reduction Agency—Joint Science and Technology Office, Medical S & T Division (MA, BEM, GAO). Research in LPDS is supported by the National Cancer Institute (NCI) and the National Institutes of Health (NIH) Intramural Research Program (YCT).
Disclaimer: The views expressed in this chapter are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the US Government.
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