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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Control of Autophagosome Axonal Retrograde Flux by Presynaptic Activity Unveiled Using Botulinum Neurotoxin Type A</title><author><name sortKey="Wang, Tong" sort="Wang, Tong" uniqKey="Wang T" first="Tong" last="Wang">Tong Wang</name><affiliation><nlm:aff id="A1">Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author><author><name sortKey="Martin, Sally" sort="Martin, Sally" uniqKey="Martin S" first="Sally" last="Martin">Sally Martin</name><affiliation><nlm:aff id="A1">Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author><author><name sortKey="Papadopulos, Andreas" sort="Papadopulos, Andreas" uniqKey="Papadopulos A" first="Andreas" last="Papadopulos">Andreas Papadopulos</name><affiliation><nlm:aff id="A1">Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author><author><name sortKey="Harper, Callista B" sort="Harper, Callista B" uniqKey="Harper C" first="Callista B." last="Harper">Callista B. Harper</name><affiliation><nlm:aff id="A1">Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author><author><name sortKey="Mavlyutov, Timur A" sort="Mavlyutov, Timur A" uniqKey="Mavlyutov T" first="Timur A." last="Mavlyutov">Timur A. Mavlyutov</name><affiliation><nlm:aff id="A4">University of Wisconsin Medical School, Madison, Wisconsin 53706</nlm:aff></affiliation></author><author><name sortKey="Niranjan, Dhevahi" sort="Niranjan, Dhevahi" uniqKey="Niranjan D" first="Dhevahi" last="Niranjan">Dhevahi Niranjan</name><affiliation><nlm:aff id="A5">Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Glass, Nick R" sort="Glass, Nick R" uniqKey="Glass N" first="Nick R." last="Glass">Nick R. Glass</name><affiliation><nlm:aff id="A2">Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author><author><name sortKey="Cooper White, Justin J" sort="Cooper White, Justin J" uniqKey="Cooper White J" first="Justin J." last="Cooper-White">Justin J. Cooper-White</name><affiliation><nlm:aff id="A2">Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A3">School of Chemical Engineering, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Materials Science and Engineering Division, Commonwealth Scientific and Industrial Research Organization, Clayton, Victoria 3169, Australia</nlm:aff></affiliation></author><author><name sortKey="Sibarita, Jean Baptiste" sort="Sibarita, Jean Baptiste" uniqKey="Sibarita J" first="Jean-Baptiste" last="Sibarita">Jean-Baptiste Sibarita</name><affiliation><nlm:aff id="A7">University of Bordeaux, Interdisciplinary Institute for Neuroscience, Unité Mixte de Recherche 5297, Bordeaux, France</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5297, Bordeaux, France</nlm:aff></affiliation></author><author><name sortKey="Choquet, Daniel" sort="Choquet, Daniel" uniqKey="Choquet D" first="Daniel" last="Choquet">Daniel Choquet</name><affiliation><nlm:aff id="A7">University of Bordeaux, Interdisciplinary Institute for Neuroscience, Unité Mixte de Recherche 5297, Bordeaux, France</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5297, Bordeaux, France</nlm:aff></affiliation><affiliation><nlm:aff id="A9">Bordeaux Imaging Center, Unité Mixte de Service 3420, Centre National de la Recherche Scientifique, US4 INSERM, University of Bordeaux, France</nlm:aff></affiliation></author><author><name sortKey="Davletov, Bazbek" sort="Davletov, Bazbek" uniqKey="Davletov B" first="Bazbek" last="Davletov">Bazbek Davletov</name><affiliation><nlm:aff id="A10">Department of Biomedical Science, The University of Sheffield, Sheffield, S10 2TN, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Meunier, Frederic A" sort="Meunier, Frederic A" uniqKey="Meunier F" first="Frédéric A." last="Meunier">Frédéric A. Meunier</name><affiliation><nlm:aff id="A1">Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25878289</idno><idno type="pmc">4787026</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4787026</idno><idno type="RBID">PMC:4787026</idno><idno type="doi">10.1523/JNEUROSCI.3757-14.2015</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">002003</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002003</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Control of Autophagosome Axonal Retrograde Flux by Presynaptic Activity Unveiled Using Botulinum Neurotoxin Type A</title><author><name sortKey="Wang, Tong" sort="Wang, Tong" uniqKey="Wang T" first="Tong" last="Wang">Tong Wang</name><affiliation><nlm:aff id="A1">Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author><author><name sortKey="Martin, Sally" sort="Martin, Sally" uniqKey="Martin S" first="Sally" last="Martin">Sally Martin</name><affiliation><nlm:aff id="A1">Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author><author><name sortKey="Papadopulos, Andreas" sort="Papadopulos, Andreas" uniqKey="Papadopulos A" first="Andreas" last="Papadopulos">Andreas Papadopulos</name><affiliation><nlm:aff id="A1">Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author><author><name sortKey="Harper, Callista B" sort="Harper, Callista B" uniqKey="Harper C" first="Callista B." last="Harper">Callista B. Harper</name><affiliation><nlm:aff id="A1">Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author><author><name sortKey="Mavlyutov, Timur A" sort="Mavlyutov, Timur A" uniqKey="Mavlyutov T" first="Timur A." last="Mavlyutov">Timur A. Mavlyutov</name><affiliation><nlm:aff id="A4">University of Wisconsin Medical School, Madison, Wisconsin 53706</nlm:aff></affiliation></author><author><name sortKey="Niranjan, Dhevahi" sort="Niranjan, Dhevahi" uniqKey="Niranjan D" first="Dhevahi" last="Niranjan">Dhevahi Niranjan</name><affiliation><nlm:aff id="A5">Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Glass, Nick R" sort="Glass, Nick R" uniqKey="Glass N" first="Nick R." last="Glass">Nick R. Glass</name><affiliation><nlm:aff id="A2">Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author><author><name sortKey="Cooper White, Justin J" sort="Cooper White, Justin J" uniqKey="Cooper White J" first="Justin J." last="Cooper-White">Justin J. Cooper-White</name><affiliation><nlm:aff id="A2">Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A3">School of Chemical Engineering, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Materials Science and Engineering Division, Commonwealth Scientific and Industrial Research Organization, Clayton, Victoria 3169, Australia</nlm:aff></affiliation></author><author><name sortKey="Sibarita, Jean Baptiste" sort="Sibarita, Jean Baptiste" uniqKey="Sibarita J" first="Jean-Baptiste" last="Sibarita">Jean-Baptiste Sibarita</name><affiliation><nlm:aff id="A7">University of Bordeaux, Interdisciplinary Institute for Neuroscience, Unité Mixte de Recherche 5297, Bordeaux, France</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5297, Bordeaux, France</nlm:aff></affiliation></author><author><name sortKey="Choquet, Daniel" sort="Choquet, Daniel" uniqKey="Choquet D" first="Daniel" last="Choquet">Daniel Choquet</name><affiliation><nlm:aff id="A7">University of Bordeaux, Interdisciplinary Institute for Neuroscience, Unité Mixte de Recherche 5297, Bordeaux, France</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5297, Bordeaux, France</nlm:aff></affiliation><affiliation><nlm:aff id="A9">Bordeaux Imaging Center, Unité Mixte de Service 3420, Centre National de la Recherche Scientifique, US4 INSERM, University of Bordeaux, France</nlm:aff></affiliation></author><author><name sortKey="Davletov, Bazbek" sort="Davletov, Bazbek" uniqKey="Davletov B" first="Bazbek" last="Davletov">Bazbek Davletov</name><affiliation><nlm:aff id="A10">Department of Biomedical Science, The University of Sheffield, Sheffield, S10 2TN, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Meunier, Frederic A" sort="Meunier, Frederic A" uniqKey="Meunier F" first="Frédéric A." last="Meunier">Frédéric A. Meunier</name><affiliation><nlm:aff id="A1">Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of neuroscience : the official journal of the Society for Neuroscience</title><idno type="ISSN">0270-6474</idno><idno type="eISSN">1529-2401</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">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 <italic>in vitro</italic> and <italic>in vivo</italic>. Blocking autophagosome formation or acidification with wortmannin or bafilomycin A<sub>1</sub>, 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.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">8102140</journal-id><journal-id journal-id-type="pubmed-jr-id">5035</journal-id><journal-id journal-id-type="nlm-ta">J Neurosci</journal-id><journal-id journal-id-type="iso-abbrev">J. Neurosci.</journal-id><journal-title-group><journal-title>The Journal of neuroscience : the official journal of the Society for Neuroscience</journal-title></journal-title-group><issn pub-type="ppub">0270-6474</issn><issn pub-type="epub">1529-2401</issn></journal-meta><article-meta><article-id pub-id-type="pmid">25878289</article-id><article-id pub-id-type="pmc">4787026</article-id><article-id pub-id-type="doi">10.1523/JNEUROSCI.3757-14.2015</article-id><article-id pub-id-type="manuscript">EMS65975</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Control of Autophagosome Axonal Retrograde Flux by Presynaptic Activity Unveiled Using Botulinum Neurotoxin Type A</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Tong</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Martin</surname><given-names>Sally</given-names></name><xref ref-type="aff" rid="A1">1</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-9294-5404</contrib-id></contrib><contrib contrib-type="author"><name><surname>Papadopulos</surname><given-names>Andreas</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Harper</surname><given-names>Callista B.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mavlyutov</surname><given-names>Timur A.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Niranjan</surname><given-names>Dhevahi</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Glass</surname><given-names>Nick R.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Cooper-White</surname><given-names>Justin J.</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Sibarita</surname><given-names>Jean-Baptiste</given-names></name><xref ref-type="aff" rid="A7">7</xref><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Choquet</surname><given-names>Daniel</given-names></name><xref ref-type="aff" rid="A7">7</xref><xref ref-type="aff" rid="A8">8</xref><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Davletov</surname><given-names>Bazbek</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Meunier</surname><given-names>Frédéric A.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib></contrib-group><aff id="A1"><label>1</label>Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia</aff><aff id="A2"><label>2</label>Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia</aff><aff id="A3"><label>3</label>School of Chemical Engineering, University of Queensland, Brisbane, Queensland 4072, Australia</aff><aff id="A4"><label>4</label>University of Wisconsin Medical School, Madison, Wisconsin 53706</aff><aff id="A5"><label>5</label>Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom</aff><aff id="A6"><label>6</label>Materials Science and Engineering Division, Commonwealth Scientific and Industrial Research Organization, Clayton, Victoria 3169, Australia</aff><aff id="A7"><label>7</label>University of Bordeaux, Interdisciplinary Institute for Neuroscience, Unité Mixte de Recherche 5297, Bordeaux, France</aff><aff id="A8"><label>8</label>Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5297, Bordeaux, France</aff><aff id="A9"><label>9</label>Bordeaux Imaging Center, Unité Mixte de Service 3420, Centre National de la Recherche Scientifique, US4 INSERM, University of Bordeaux, France</aff><aff id="A10"><label>10</label>Department of Biomedical Science, The University of Sheffield, Sheffield, S10 2TN, United Kingdom</aff><author-notes><corresp id="CR1">Correspondence should be addressed to Frédéric A. Meunier Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia. <email>f.meunier@uq.edu.au</email></corresp><fn id="FN1"><p id="P1">Author contributions: T.W., S.M., A.P., C.B.H., T.A.M., B.D., and F.A.M. designed research; T.W., S.M., C.B.H., T.A.M., D.N., and N.R.G. performed research; C.B.H., N.R.G., J.J.C.-W., J.-B.S., and D.C. contributed unpublished reagents/analytic tools; T.W., S.M., and A.P. analyzed data; T.W., S.M., A.P., C.B.H., T.A.M., N.R.G., B.D., and F.A.M. wrote the paper.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>17</day><month>11</month><year>2015</year></pub-date><pub-date pub-type="ppub"><day>15</day><month>4</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>11</day><month>3</month><year>2016</year></pub-date><volume>35</volume><issue>15</issue><fpage>6179</fpage><lpage>6194</lpage><pmc-comment>elocation-id from pubmed: 10.1523/JNEUROSCI.3757-14.2015</pmc-comment>
<abstract><p id="P2">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 <italic>in vitro</italic> and <italic>in vivo</italic>. Blocking autophagosome formation or acidification with wortmannin or bafilomycin A<sub>1</sub>, 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.</p></abstract><kwd-group><kwd>autophagosome</kwd><kwd>axon</kwd><kwd>Botulinum neurotoxin</kwd><kwd>presynaptic</kwd><kwd>retrograde transport</kwd><kwd>synaptic vesicle</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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