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

Luis Fonseca-Ornelas, Sybille E. Eisbach, Maria Paulat, Karin Giller, Claudio O. Fernández, Tiago F. Outeiro, Stefan Becker and Markus Zweckstetter ()
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Luis Fonseca-Ornelas: Max Planck Institute for Biophysical Chemistry
Sybille E. Eisbach: University Medicine
Maria Paulat: Max Planck Institute for Biophysical Chemistry
Karin Giller: Max Planck Institute for Biophysical Chemistry
Claudio O. Fernández: Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR), Universidad Nacional de Rosario
Tiago F. Outeiro: University Medicine
Stefan Becker: Max Planck Institute for Biophysical Chemistry
Markus Zweckstetter: Max Planck Institute for Biophysical Chemistry

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6857

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