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Nat Commun. 2014 Dec 19;5:5857. doi: 10.1038/ncomms6857.

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

Author information

1
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
2
Department of Neurodegeneration and Restorative Research, University Medicine, Waldweg 33, 37073 Göttingen, Germany.
3
1] Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR), Universidad Nacional de Rosario, 27 de Febrero 210 bis, S2002LRK- Rosario, Argentina [2] Instituto de Investigaciones para el Descubrimiento de Farmacos de Rosario-IIDEFAR, (CONICET-UNR), 27 de Febrero 210 bis, S2002LRK- Rosario, Argentina.
4
1] Department of Neurodegeneration and Restorative Research, University Medicine, Waldweg 33, 37073 Göttingen, Germany [2] DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center, 37073 Göttingen, Germany.
5
1] Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany [2] DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center, 37073 Göttingen, Germany [3] German Center for Neurodegenerative Diseases (DZNE), Am Fassberg 11, 37077 Göttingen, Germany.

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.

PMID:
25524885
DOI:
10.1038/ncomms6857
[Indexed for MEDLINE]

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