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@ARTICLE{Hoffmann:140581,
      author       = {Hoffmann, Sheila and Orlando, Marta and Andrzejak, Ewa and
                      Bruns, Christine and Trimbuch, Thorsten and Rosenmund,
                      Christian and Garner, Craig C and Ackermann, Frauke},
      title        = {{L}ight-{A}ctivated {ROS} {P}roduction {I}nduces {S}ynaptic
                      {A}utophagy.},
      journal      = {The journal of neuroscience},
      volume       = {39},
      number       = {12},
      issn         = {0270-6474},
      address      = {Washington, DC},
      publisher    = {Soc.57413},
      reportid     = {DZNE-2020-06903},
      pages        = {2163-2183},
      year         = {2019},
      abstract     = {The 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.},
      keywords     = {Animals / Autophagy: physiology / Female / HEK293 Cells /
                      HeLa Cells / Hippocampus: metabolism / Hippocampus:
                      ultrastructure / Humans / Male / Mice, Inbred C57BL /
                      Neurons: metabolism / Neurons: ultrastructure / Presynaptic
                      Terminals: metabolism / Presynaptic Terminals:
                      ultrastructure / Reactive Oxygen Species: metabolism /
                      Synaptic Vesicles: metabolism / Synaptic Vesicles:
                      ultrastructure},
      cin          = {AG Garner / AG Ackermann},
      ddc          = {610},
      cid          = {I:(DE-2719)1810001 / I:(DE-2719)1813004},
      pnm          = {341 - Molecular Signaling (POF3-341)},
      pid          = {G:(DE-HGF)POF3-341},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30655355},
      pmc          = {pmc:PMC6433757},
      doi          = {10.1523/JNEUROSCI.1317-18.2019},
      url          = {https://pub.dzne.de/record/140581},
}