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@ARTICLE{Schmidt:136596,
      author       = {Schmidt, Felix and Levin, Johannes and Kamp, Frits and
                      Kretzschmar, Hans and Giese, Armin and Bötzel, Kai},
      title        = {{S}ingle-channel electrophysiology reveals a distinct and
                      uniform pore complex formed by α-synuclein oligomers in
                      lipid membranes.},
      journal      = {PLOS ONE},
      volume       = {7},
      number       = {8},
      issn         = {1932-6203},
      address      = {San Francisco, California, US},
      publisher    = {PLOS},
      reportid     = {DZNE-2020-02918},
      pages        = {e42545},
      year         = {2012},
      abstract     = {Synucleinopathies such as Parkinson's disease, multiple
                      system atrophy and dementia with Lewy bodies are
                      characterized by deposition of aggregated α-synuclein.
                      Recent findings indicate that pathological oligomers rather
                      than fibrillar aggregates may represent the main toxic
                      protein species. It has been shown that α-synuclein
                      oligomers can increase the conductance of lipid bilayers
                      and, in cell-culture, lead to calcium dyshomeostasis and
                      cell death. In this study, employing a setup for
                      single-channel electrophysiology, we found that addition of
                      iron-induced α-synuclein oligomers resulted in quantized
                      and stepwise increases in bilayer conductance indicating
                      insertion of distinct transmembrane pores. These pores
                      switched between open and closed states depending on clamped
                      voltage revealing a single-pore conductance comparable to
                      that of bacterial porins. Pore conductance was dependent on
                      transmembrane potential and the available cation. The pores
                      stably inserted into the bilayer and could not be removed by
                      buffer exchange. Pore formation could be inhibited by
                      co-incubation with the aggregation inhibitor baicalein. Our
                      findings indicate that iron-induced α-synuclein oligomers
                      can form a uniform and distinct pore species with
                      characteristic electrophysiological properties. Pore
                      formation could be a critical event in the pathogenesis of
                      synucleinopathies and provide a novel structural target for
                      disease-modifying therapy.},
      keywords     = {Cations / Electric Conductivity / Electrophysiological
                      Phenomena / Humans / Lipid Bilayers: metabolism / Models,
                      Biological / Porosity / Protein Structure, Quaternary / Time
                      Factors / alpha-Synuclein: chemistry / alpha-Synuclein:
                      metabolism / Cations (NLM Chemicals) / Lipid Bilayers (NLM
                      Chemicals) / alpha-Synuclein (NLM Chemicals)},
      cin          = {AG Höglinger 1},
      ddc          = {610},
      cid          = {I:(DE-2719)1110002},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:22880029},
      pmc          = {pmc:PMC3411845},
      doi          = {10.1371/journal.pone.0042545},
      url          = {https://pub.dzne.de/record/136596},
}