title: Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers.
abstract: BACKGROUND
  In several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn), implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics demonstrated a protective effect of phosphorylation. Since metal-ion induced asyn oligomers were identified as a potential neurotoxic aggregate species with membrane pore-forming abilities, the current study was undertaken to determine effects of asyn phosphorylation on oligomer membrane binding.
  
  
  METHODS
  We investigated the influence of S129 phosphorylation on interactions of metal-ion induced asyn oligomers with small unilamellar lipid vesicles (SUV) composed of POPC and DPPC applying the phosphorylation mimic asyn129E. Confocal single-particle fluorescence techniques were used to monitor membrane binding at the single-particle level.
  
  
  RESULTS
  Binding of asyn129E monomers to gel-state membranes (DPPC-SUV) is slightly reduced compared to wild-type asyn, while no interactions with membranes in the liquid-crystalline state (POPC-SUV) are seen for both asyn and asyn129E. Conversely, metal-ion induced oligomer formation is markedly increased in asyn129E. Surprisingly, membrane binding to POPC-SUV is nearly absent in Fe(3+) induced asyn129E oligomers and markedly reduced in Al(3+) induced oligomers.
  
  
  CONCLUSIONS
  The protective effect of pseudophosphorylation seen in animal models may be due to impeded oligomer membrane binding. Phosphorylation at Ser129 may thus have a protective effect against neurotoxic asyn oligomers by preventing oligomer membrane binding and disruption of the cellular electrophysiological equilibrium. Importantly, these findings put a new complexion on experimental pharmaceutical interventions against POLO-2 kinase.
authors.affiliation: Department of Neurology, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany; Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany; Department of Palliative Medicine, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Georg Sebastian
authors.initials: GS
authors.lastname: Nübling
authors.affiliation: Department of Neurology, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Levin
authors.affiliation: Department of Neurology, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bader
authors.affiliation: Department of Neurology, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany; Department of Palliative Medicine, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany; Endowed Professorship for Interdisciplinary Research in Palliative Care, Institute of Nursing Science and -Practice, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorenzl
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hillmer
authors.affiliation: Department of Neurology, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Högen
authors.affiliation: Adolf-Butenandt-Institute, Munich, Germany.
authors.forename: Frits
authors.initials: F
authors.lastname: Kamp
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010713:Phosphatidylcholines / Q000378:metabolism; D010766:Phosphorylation; D016062:Porosity; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D012694:Serine / Q000378:metabolism*; D013696:Temperature; D053835:Unilamellar Liposomes / Q000737:chemistry / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D010713:Phosphatidylcholines; D053835:Unilamellar Liposomes; D051844:alpha-Synuclein; D015060:1,2-Dipalmitoylphosphatidylcholine; D012694:Serine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine