Small molecule-mediated stabilization of vesicle-associated helical alpha-synuclein inhibits pathogenic misfolding and aggregation
2014 | journal article. A publication with affiliation to the University of Göttingen.
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Small molecule-mediated stabilization of vesicle-associated helical alpha-synuclein inhibits pathogenic misfolding and aggregation
Fonseca-Ornelas, L.; Eisbach, S. E.; Paulat, M.; Giller, K.; Fernandez, C. O.; Outeiro, T. F. & Becker, S. et al. (2014)
Nature Communications, 5 art. 5857. DOI: https://doi.org/10.1038/ncomms6857
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- Authors
- Fonseca-Ornelas, Luis; Eisbach, Sibylle E.; Paulat, Maria; Giller, Karin; Fernandez, Claudio O.; Outeiro, Tiago Fleming ; Becker, Stefan; Zweckstetter, Markus
- Abstract
- alpha-synuclein is an abundant presynaptic protein that is important for regulation of synaptic vesicle trafficking, and whose misfolding plays a key role in Parkinson's disease. While alpha-synuclein is disordered in solution, it folds into a helical conformation when bound to synaptic vesicles. Stabilization of helical, folded alpha-synuclein might therefore interfere with alpha-synuclein-induced neurotoxicity. Here we show that several small molecules, which delay aggregation of alpha-synuclein in solution, including the Parkinson's disease drug selegiline, fail to interfere with misfolding of vesicle-bound alpha-synuclein. In contrast, the porphyrin phtalocyanine tetrasulfonate directly binds to vesicle-bound alpha-synuclein, stabilizes its helical conformation and thereby delays pathogenic misfolding and aggregation. Our study suggests that small-molecule-mediated stabilization of helical vesicle-bound alpha-synuclein opens new possibilities to target Parkinson's disease and related synucleinopathies.
- Issue Date
- 2014
- Status
- published
- Publisher
- Nature Publishing Group
- Journal
- Nature Communications
- ISSN
- 2041-1723