title: Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with α-synuclein at the single molecule level.
abstract: BACKGROUND
  Fibrillar amyloid-like deposits and co-deposits of tau and α-synuclein are found in several common neurodegenerative diseases. Recent evidence indicates that small oligomers are the most relevant toxic aggregate species. While tau fibril formation is well-characterized, factors influencing tau oligomerization and molecular interactions of tau and α-synuclein are not well understood.
  
  
  RESULTS
  We used a novel approach applying confocal single-particle fluorescence to investigate the influence of tau phosphorylation and metal ions on tau oligomer formation and its coaggregation with α-synuclein at the level of individual oligomers. We show that Al3+ at physiologically relevant concentrations and tau phosphorylation by GSK-3β exert synergistic effects on the formation of a distinct SDS-resistant tau oligomer species even at nanomolar protein concentration. Moreover, tau phosphorylation and Al3+ as well as Fe3+ enhanced both formation of mixed oligomers and recruitment of α-synuclein in pre-formed tau oligomers.
  
  
  CONCLUSIONS
  Our findings provide a new perspective on interactions of tau phosphorylation, metal ions, and the formation of potentially toxic oligomer species, and elucidate molecular crosstalks between different aggregation pathways involved in neurodegeneration.
authors: Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Feodor-Lynen-Str, 23, 81377, Munich, Germany.
authors: Georg
authors: G
authors: Nübling
authors: Benedikt
authors: B
authors: Bader
authors: Johannes
authors: J
authors: Levin
authors: Jenna
authors: J
authors: Hildebrandt
authors: Hans
authors: H
authors: Kretzschmar
authors: Armin
authors: A
authors: Giese
mesh_terms: D045744:Cell Line, Tumor; D004926:Escherichia coli; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007501:Iron / Q000737:chemistry; D008670:Metals / Q000737:chemistry*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010766:Phosphorylation; D055503:Protein Multimerization; D012997:Solvents / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D008670:Metals; D012997:Solvents; D051844:alpha-Synuclein; D016875:tau Proteins; D007501:Iron; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3