Single particle characterization of iron-induced pore-forming α-synuclein oligomers

Marcus Kostka, Tobias Högen, Karin M. Danzer, Johannes Levin, Matthias Habeck, Andreas Wirth, Richard Wagner, Charles G. Glabe, Sabine Finger, Udo Heinzelmann, Patrick Garidel, Wenzhen Duan, Christopher A. Ross, Hans Kretzschmar, Armin Giese

Research output: Contribution to journalArticle

Abstract

Aggregation of α-synuclein is a key event in several neurodegenerative diseases, including Parkinson disease. Recent findings suggest that oligomers represent the principal toxic aggregate species. Using confocal single-molecule fluorescence techniques, such as scanning for intensely fluorescent targets (SIFT) and atomic force microscopy, we monitored α-synuclein oligomer formation at the single particle level. Organic solvents were used to trigger aggregation, which resulted in small oligomers ("intermediate I"). Under these conditions, Fe3+ at low micromolar concentrations dramatically increased aggregation and induced formation of larger oligomers ("intermediate II"). Both oligomer species were on-pathway to amyloid fibrils and could seed amyloid formation. Notably, only Fe3+-induced oligomers were SDS-resistant and could form ion-permeable pores in a planar lipid bilayer, which were inhibited by the oligomer-specific A11 antibody. Moreover, baicalein and N′-benzylidene- benzohydrazide derivatives inhibited oligomer formation. Baicalein also inhibited α-synuclein-dependent toxicity in neuronal cells. Our results may provide a potential disease mechanism regarding the role of ferric iron and of toxic oligomer species in Parkinson diseases. Moreover, scanning for intensely fluorescent targets allows high throughput screening for aggregation inhibitors and may provide new approaches for drug development and therapy.

Original languageEnglish (US)
Pages (from-to)10992-11003
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number16
DOIs
StatePublished - Apr 18 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kostka, M., Högen, T., Danzer, K. M., Levin, J., Habeck, M., Wirth, A., Wagner, R., Glabe, C. G., Finger, S., Heinzelmann, U., Garidel, P., Duan, W., Ross, C. A., Kretzschmar, H., & Giese, A. (2008). Single particle characterization of iron-induced pore-forming α-synuclein oligomers. Journal of Biological Chemistry, 283(16), 10992-11003. https://doi.org/10.1074/jbc.M709634200