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000140581 0247_ $$2doi$$a10.1523/JNEUROSCI.1317-18.2019
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000140581 041__ $$aEnglish
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000140581 1001_ $$0P:(DE-2719)2811236$$aHoffmann, Sheila$$b0$$eFirst author$$udzne
000140581 245__ $$aLight-Activated ROS Production Induces Synaptic Autophagy.
000140581 260__ $$aWashington, DC$$bSoc.57413$$c2019
000140581 264_1 $$2Crossref$$3online$$bSociety for Neuroscience$$c2019-01-17
000140581 264_1 $$2Crossref$$3print$$bSociety for Neuroscience$$c2019-03-20
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000140581 520__ $$aThe regulated turnover of synaptic vesicle (SV) proteins is thought to involve the ubiquitin-dependent tagging and degradation through endo-lysosomal and autophagy pathways. Yet, it remains unclear which of these pathways are used, when they become activated, and whether SVs are cleared en masse together with SV proteins or whether both are degraded selectively. Equally puzzling is how quickly these systems can be activated and whether they function in real-time to support synaptic health. To address these questions, we have developed an imaging-based system that simultaneously tags presynaptic proteins while monitoring autophagy. Moreover, by tagging SV proteins with a light-activated ROS generator, Supernova, it was possible to temporally control the damage to specific SV proteins and assess their consequence to autophagy-mediated clearance mechanisms and synaptic function. Our results show that, in mouse hippocampal neurons of either sex, presynaptic autophagy can be induced in as little as 5-10 min and eliminates primarily the damaged protein rather than the SV en masse. Importantly, we also find that autophagy is essential for synaptic function, as light-activated damage to, for example, Synaptophysin only compromises synaptic function when autophagy is simultaneously blocked. These data support the concept that presynaptic boutons have a robust highly regulated clearance system to maintain not only synapse integrity, but also synaptic function.SIGNIFICANCE STATEMENT The real-time surveillance and clearance of synaptic proteins are thought to be vital to the health, functionality, and integrity of vertebrate synapses and are compromised in neurodegenerative disorders, yet the fundamental mechanisms regulating these systems remain enigmatic. Our analysis reveals that presynaptic autophagy is a critical part of a real-time clearance system at synapses capable of responding to local damage of synaptic vesicle proteins within minutes and to be critical for the ongoing functionality of these synapses. These data indicate that synapse autophagy is not only locally regulated but also crucial for the health and functionality of vertebrate presynaptic boutons.
000140581 536__ $$0G:(DE-HGF)POF3-341$$a341 - Molecular Signaling (POF3-341)$$cPOF3-341$$fPOF III$$x0
000140581 542__ $$2Crossref$$i2019-09-20$$uhttps://creativecommons.org/licenses/by-nc-sa/4.0/
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000140581 650_2 $$2MeSH$$aAnimals
000140581 650_2 $$2MeSH$$aAutophagy: physiology
000140581 650_2 $$2MeSH$$aFemale
000140581 650_2 $$2MeSH$$aHEK293 Cells
000140581 650_2 $$2MeSH$$aHeLa Cells
000140581 650_2 $$2MeSH$$aHippocampus: metabolism
000140581 650_2 $$2MeSH$$aHippocampus: ultrastructure
000140581 650_2 $$2MeSH$$aHumans
000140581 650_2 $$2MeSH$$aMale
000140581 650_2 $$2MeSH$$aMice, Inbred C57BL
000140581 650_2 $$2MeSH$$aNeurons: metabolism
000140581 650_2 $$2MeSH$$aNeurons: ultrastructure
000140581 650_2 $$2MeSH$$aPresynaptic Terminals: metabolism
000140581 650_2 $$2MeSH$$aPresynaptic Terminals: ultrastructure
000140581 650_2 $$2MeSH$$aReactive Oxygen Species: metabolism
000140581 650_2 $$2MeSH$$aSynaptic Vesicles: metabolism
000140581 650_2 $$2MeSH$$aSynaptic Vesicles: ultrastructure
000140581 7001_ $$aOrlando, Marta$$b1
000140581 7001_ $$0P:(DE-2719)2811708$$aAndrzejak, Ewa$$b2$$udzne
000140581 7001_ $$0P:(DE-2719)2811027$$aBruns, Christine$$b3$$udzne
000140581 7001_ $$aTrimbuch, Thorsten$$b4
000140581 7001_ $$aRosenmund, Christian$$b5
000140581 7001_ $$0P:(DE-2719)2810922$$aGarner, Craig C$$b6$$udzne
000140581 7001_ $$0P:(DE-2719)2810967$$aAckermann, Frauke$$b7$$eLast author$$udzne
000140581 77318 $$2Crossref$$3journal-article$$a10.1523/jneurosci.1317-18.2019$$bSociety for Neuroscience$$d2019-01-17$$n12$$p2163-2183$$tThe Journal of Neuroscience$$v39$$x0270-6474$$y2019
000140581 773__ $$0PERI:(DE-600)1475274-8$$a10.1523/JNEUROSCI.1317-18.2019$$gVol. 39, no. 12, p. 2163 - 2183$$n12$$p2163-2183$$q39:12<2163 - 2183$$tThe journal of neuroscience$$v39$$x0270-6474$$y2019
000140581 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433757
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000140581 9141_ $$y2019
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