Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type A

Wang, Tong, Martin, Sally, Papadopulos, Andreas, Harper, Callista B., Mavlyutov, Timur A., Niranjan, Dhevahi, Glass, Nick R., Cooper-White, Justin J., Sibarita, Jean-Baptiste, Choquet, Daniel, Davletov, Bazbek and Meunier, Frederic A. (2015) Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type A. Journal of Neuroscience, 35 15: 6179-6194. doi:10.1523/JNEUROSCI.3757-14.2015

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Author Wang, Tong
Martin, Sally
Papadopulos, Andreas
Harper, Callista B.
Mavlyutov, Timur A.
Niranjan, Dhevahi
Glass, Nick R.
Cooper-White, Justin J.
Sibarita, Jean-Baptiste
Choquet, Daniel
Davletov, Bazbek
Meunier, Frederic A.
Title Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type A
Journal name Journal of Neuroscience   Check publisher's open access policy
ISSN 1529-2401
Publication date 2015-04-15
Year available 2015
Sub-type Article (original research)
DOI 10.1523/JNEUROSCI.3757-14.2015
Open Access Status File (Publisher version)
Volume 35
Issue 15
Start page 6179
End page 6194
Total pages 16
Place of publication Washington, DC United States
Publisher Society for Neuroscience
Language eng
Abstract Botulinum neurotoxin type A (BoNT/A) is a highly potent neurotoxin that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. However, recent evidence suggests that the neurotoxic activity of BoNT/A is not restricted to the periphery, but also reaches the CNS after retrograde axonal transport. Because BoNT/A is internalized in recycling synaptic vesicles, it is unclear which compartment facilitates this transport. Using live-cell confocal and single-molecule imaging of rat hippocampal neurons cultured in microfluidic devices, we show that the activity-dependent uptake of the binding domain of the BoNT/A heavy chain (BoNT/A-Hc) is followed by a delayed increase in retrograde axonal transport of BoNT/A-Hc carriers. Consistent with a role of presynaptic activity in initiating transport of the active toxin, activity-dependent uptake of BoNT/A in the terminal led to a significant increase in SNAP25 cleavage detected in the soma chamber compared with nonstimulated neurons. Surprisingly, most endocytosed BoNT/A-Hc was incorporated into LC3-positive autophagosomes generated in the nerve terminals, which then underwent retrograde transport to the cell soma, where they fused with lysosomes both in vitro and in vivo. Blocking autophagosome formation or acidification with wortmannin or bafilomycin A1, respectively, inhibited the activity-dependent retrograde trafficking of BoNT/A-Hc. Our data demonstrate that both the presynaptic formation of autophagosomes and the initiation of their retrograde trafficking are tightly regulated by presynaptic activity.
Keyword Autophagosome
Botulinum neurotoxin
Retrograde transport
Synaptic vesicle
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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