Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 16, Pages 10992-11003Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M709634200
Keywords
-
Categories
Funding
- NINDS NIH HHS [R21 NS055971] Funding Source: Medline
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available