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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., 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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-E552-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CC75-F
Genre: Journal Article

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Fonseca-Ornelas, L.1, Author              
Eisbach, S. E., Author
Paulat, M.2, Author              
Giller, K.2, Author              
Fernandez, C. O., Author
Outeiro, T. F., Author
Becker, S.2, Author              
Zweckstetter, M.1, Author              
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              
2Department of NMR-Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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 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.

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Language(s): eng - English
 Dates: 2014-12-19
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1038/ncomms6857
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Title: Nature Communications
Source Genre: Journal
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Pages: 11 Volume / Issue: 5 Sequence Number: 5857 Start / End Page: - Identifier: -