Botulinum neurotoxin type-A enters a non-recycling pool of synaptic vesicles.

Callista B. Harper, Andreas Papadopulos, Sally Martin, Daniel R. Matthews, Garry P. Morgan, Tam H. Nguyen, Tong Wang, Deepak Nair, Daniel Choquet, Frederic A. Meunier
Sci Rep. 2016-01-25; 6(1):
DOI: 10.1038/srep19654

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1. Sci Rep. 2016 Jan 25;6:19654. doi: 10.1038/srep19654.

Botulinum neurotoxin type-A enters a non-recycling pool of synaptic vesicles.

Harper CB(1), Papadopulos A(1), Martin S(1), Matthews DR(2), Morgan GP(3), Nguyen
TH(1), Wang T(1), Nair D(4)(5), Choquet D(4), Meunier FA(1).

Author information:
(1)The University of Queensland, Queensland Brain Institute, Clem Jones Centre
for Ageing Dementia Research, Brisbane, Queensland 4072, Australia.
(2)The University of Queensland, Queensland Brain Institute, Brisbane, Queensland
4072, Australia.
(3)The University of Queensland, Centre for Microscopy and Microanalysis,
Brisbane, Queensland 4072, Australia.
(4)Interdisciplinary Institute for Neuroscience, The University of Bordeaux,
Bordeaux, 33000, France.
(5)Centre for Neuroscience, Indian Institute of Science, Bangalore, 560012,

Neuronal communication relies on synaptic vesicles undergoing regulated
exocytosis and recycling for multiple rounds of fusion. Whether all synaptic
vesicles have identical protein content has been challenged, suggesting that
their recycling ability may differ greatly. Botulinum neurotoxin type-A (BoNT/A)
is a highly potent neurotoxin that is internalized in synaptic vesicles at motor
nerve terminals and induces flaccid paralysis. Recently, BoNT/A was also shown to
undergo retrograde transport, suggesting it might enter a specific pool of
synaptic vesicles with a retrograde trafficking fate. Using high-resolution
microscopy techniques including electron microscopy and single molecule imaging,
we found that the BoNT/A binding domain is internalized within a subset of
vesicles that only partially co-localize with cholera toxin B-subunit and have
markedly reduced VAMP2 immunoreactivity. Synaptic vesicles loaded with
pHrodo-BoNT/A-Hc exhibited a significantly reduced ability to fuse with the
plasma membrane in mouse hippocampal nerve terminals when compared with
pHrodo-dextran-containing synaptic vesicles and pHrodo-labeled anti-GFP
nanobodies bound to VAMP2-pHluorin or vGlut-pHluorin. Similar results were also
obtained at the amphibian neuromuscular junction. These results reveal that
BoNT/A is internalized in a subpopulation of synaptic vesicles that are not
destined to recycle, highlighting the existence of significant molecular and
functional heterogeneity between synaptic vesicles.

DOI: 10.1038/srep19654
PMCID: PMC4726273
PMID: 26805017 [Indexed for MEDLINE]

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