Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers
Autor(en): | Kostka, Marcus Hoegen, Tobias Danzer, Karin M. Levin, Johannes Habeck, Matthias Wirth, Andreas Wagner, Richard Glabe, Charles G. Finger, Sabine Heinzelmann, Udo Garidel, Patrick Duan, Wenzhen Ross, Christopher A. Kretzschmar, Hans Giese, Armin |
Stichwörter: | Biochemistry & Molecular Biology; COMMON MECHANISM; INTENSELY FLUORESCENT TARGETS; METAL-IONS; NEURODEGENERATIVE DISEASES; PARKINSONS-DISEASE; PRION PROTEIN; PROTEIN MISFOLDING DISEASES; SOLUBLE AMYLOID OLIGOMERS; TRANSGENIC MICE; VESICLE PERMEABILIZATION | Erscheinungsdatum: | 2008 | Herausgeber: | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Enthalten in: | JOURNAL OF BIOLOGICAL CHEMISTRY | Band: | 283 | Ausgabe: | 16 | Startseite: | 10992 | Seitenende: | 11003 | Zusammenfassung: | Aggregation of alpha-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 alpha-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'-benzylidenebenzohydrazide derivatives inhibited oligomer formation. Baicalein also inhibited alpha-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. |
DOI: | 10.1074/jbc.M709634200 |
Zur Langanzeige
Seitenaufrufe
2
Letzte Woche
0
0
Letzter Monat
0
0
geprüft am 06.06.2024