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Journal Article

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

MPS-Authors
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Fonseca-Ornelas,  L.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Paulat,  M.
Department of NMR-Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Giller,  K.
Department of NMR-Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Becker,  S.
Department of NMR-Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Zweckstetter,  M.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

Fulltext (public)

2104394.pdf
(Publisher version), 3MB

Supplementary Material (public)

2104394_Suppl.pdf
(Supplementary material), 2MB

Citation

Fonseca-Ornelas, L., Eisbach, S. E., Paulat, M., Giller, K., Fernandez, C. O., Outeiro, T. F., et al. (2014). Small molecule-mediated stabilization of vesicle-associated helical alpha-synuclein inhibits pathogenic misfolding and aggregation. Nature Communications, 5: 5857. doi:10.1038/ncomms6857.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0024-E552-F
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.