Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism

Harper, Callista B., Martin, Sally, Nguyen, Tam H., Daniels, Shari J., Lavidis, Nickolas A., Popoff, Michel R., Hadzic, Gordana, Mariana, Anna, Chau, Ngoc, McCluskey, Adam, Robinson, Phillip J. and Meunier, Frederic A. (2011) Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism. Journal of Biological Chemistry, 286 41: 35966-35976. doi:10.1074/jbc.M111.283879

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Author Harper, Callista B.
Martin, Sally
Nguyen, Tam H.
Daniels, Shari J.
Lavidis, Nickolas A.
Popoff, Michel R.
Hadzic, Gordana
Mariana, Anna
Chau, Ngoc
McCluskey, Adam
Robinson, Phillip J.
Meunier, Frederic A.
Title Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2011-10-01
Sub-type Article (original research)
DOI 10.1074/jbc.M111.283879
Open Access Status File (Publisher version)
Volume 286
Issue 41
Start page 35966
End page 35976
Total pages 11
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2012
Language eng
Formatted abstract
The botulinum neurotoxins (BoNTs) are di-chain bacterial proteins responsible for the paralytic disease botulism. Following binding to the plasma membrane of cholinergic motor nerve terminals, BoNTs are internalized into an endocytic compartment. Although several endocytic pathways have been characterized in neurons, the molecular mechanism underpinning the uptake of BoNTs at the presynaptic nerve terminal is still unclear. Here, a recombinant BoNT/A heavy chain binding domain (Hc) was used to unravel the internalization pathway by fluorescence and electron microscopy. BoNT/A-Hc initially enters cultured hippocampal neurons in an activity-dependent manner into synaptic vesicles and clathrin-coated vesicles before also entering endosomal structures and multivesicular bodies.Wefound that inhibiting dynamin with the novel potent Dynasore analog, Dyngo-4aTM, was sufficient to abolish BoNT/A-Hc internalization and BoNT/A-induced SNAP25 cleavage in hippocampal neurons. Dyngo-4a also interfered with BoNT/A-Hc internalization into motor nerve terminals. Furthermore, Dyngo-4a afforded protection against BoNT/A-induced paralysis at the rat hemidiaphragm. A significant delay of>30% in the onset of botulism was observed in mice injected with Dyngo-4a. Dynamin inhibition therefore provides a therapeutic avenue for the treatment of botulism and other diseases caused by pathogens sharing dynamin-dependent uptake mechanisms.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2012 Collection
School of Biomedical Sciences Publications
 
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Created: Sat, 15 Oct 2011, 03:39:07 EST by Mr Tam Nguyen on behalf of Queensland Brain Institute