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Small molecule-mediated stabilization of vesicle-associated helical α-synuclein inhibits pathogenic misfolding and aggregation

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

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.

Publication metadata

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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