Botulinum neurotoxins are a family of seven bacterial toxins (BoNT/A-G) that cause the disease botulism in humans and animals. They target neurons and cleave host proteins required for synaptic vesicle exocytosis, thereby blocking synaptic transmission and paralyzing the hosts. This mode of action and its role in pathogenesis has been well established. Humans used to get exposed to BoNTs mainly via food poisoning, but significant changes have occurred in human- BoNT interactions. First, medical advances can now revive previously untreatable patients from acute BoNT actions. Second, BoNTs are utilized as therapeutics to target neurons via local injections over long periods of time. These changes have raised the critical need to examine the additional long-term consequences of exposure to BoNTs. Indeed, previous reports and our preliminary studies have revealed that a subset of BoNTs may induce degeneration of cultured rodent neurons in addition to blocking synaptic vesicle exocytosis.
In Aim 1, we will examine whether BoNTs may induce degeneration of human neurons and in in vivo rodent models that mimic therapeutic applications. We will also investigate whether human genetic variations might render certain populations susceptible to potential cytotoxicity from the major therapeutic toxin BoNT/A.
In Aim 2, we will examine our hypothesis that BoNTs induce neurodegeneration because their substrates play an essential role in maintaining the membrane balance at plasma membranes.
Aim 1 will provide a solid foundation for establishing the potential clinical relevance.
Aim 2 will provide a mechanistic understanding for BoNT cytotoxicity. Together, these studies will establish neuronal cytotoxicity as a "newly emerged" long-term consequence due to changes in BoNT-human interactions, with significant implications for understanding long-term effects of botulism in patients and for ensuring the safety of using BoNTs as therapeutic toxins.

Public Health Relevance

Botulinum neurotoxins are one of the most dangerous potential bioterrorism agents and are also used as therapeutics. They are well-known for their ability to block synaptic vesicle exocytosis, but it has remained controversial whether members of botulinum neurotoxins might also induce neurodegeneration. Here we will investigate the potential cytotoxicity of botulinum neurotoxins and understand its mechanism, with the goal to establish the long-term consequences of BoNT action and to ensure the safety of toxin therapeutic applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS080833-01A1
Application #
8524476
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Jett, David A
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$382,813
Indirect Cost
$164,063
Name
Harvard University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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Berntsson, Ronnie Per-Arne; Peng, Lisheng; Svensson, Linda Marie et al. (2013) Crystal structures of botulinum neurotoxin DC in complex with its protein receptors synaptotagmin I and II. Structure 21:1602-11
Berntsson, Ronnie P-A; Peng, Lisheng; Dong, Min et al. (2013) Structure of dual receptor binding to botulinum neurotoxin B. Nat Commun 4:2058