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Lookup NU author(s): Professor Tiago OuteiroORCiD
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α-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 α-synuclein is disordered in solution, it folds into a helical conformation when bound to synaptic vesicles. Stabilization of helical, folded α-synuclein might therefore interfere with α-synuclein-induced neurotoxicity. Here we show that several small molecules, which delay aggregation of α-synuclein in solution, including the Parkinson's disease drug selegiline, fail to interfere with misfolding of vesicle-bound α-synuclein. In contrast, the porphyrin phtalocyanine tetrasulfonate directly binds to vesicle-bound α-synuclein, stabilizes its helical conformation and thereby delays pathogenic misfolding and aggregation. Our study suggests that small-molecule-mediated stabilization of helical vesicle-bound α-synuclein opens new possibilities to target Parkinson's disease and related synucleinopathies.
Author(s): Fonseca-Ornelas L, Eisbach SE, Paulat M, Giller K, Fernandez CO, Outeiro TF, Becker S, Zweckstetter M
Publication type: Article
Publication status: Published
Journal: Nature communications
Year: 2014
Volume: 5
Online publication date: 19/12/2014
Acceptance date: 13/11/2014
ISSN (print): 2041-1723
Publisher: Nature
URL: https://doi.org/10.1038/ncomms6857
DOI: 10.1038/ncomms6857
PubMed id: 25524885
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