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Unraveling amyloid formation paths of Parkinson's disease protein α-synuclein triggered by anionic vesicles

  • Juris Kiskis (a1), Istvan Horvath (a1), Pernilla Wittung-Stafshede (a1) and Sandra Rocha (a1)

Abstract

Amyloid formation of the synaptic brain protein α-synuclein (αS) is related to degeneration of dopaminergic neurons in Parkinson's disease patients. αS is thought to function in vesicle transport and fusion and it binds strongly to negatively charged vesicles in vitro. Here we combined circular dichroism, fluorescence and imaging methods in vitro to characterize the interaction of αS with negatively charged vesicles of DOPS (1,2-dioleoyl-sn-glycero-3-phospho-L-serine, sodium salt) and DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol), sodium salt) and the consequences of such interactions on αS amyloid formation. We found that lipid head-group chemistry modulates αS interactions and also affects amyloid fiber formation. During the course of the experiments, we made the unexpected discovery that pre-formed αS oligomers, typically present in a small amount in the αS starting material, acted as templates for linear growth of anomalous amyloid fibers in the presence of vesicles. At the same time, the remaining αS monomers were restricted from vesicle-mediated nucleation of amyloid fibers. Although not a dominant process in bulk experiments, this hidden αS aggregation pathway may be of importance in vivo.

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This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

Corresponding author

*Authors for correspondence: Pernilla Wittung-Stafshede and Sandra Rocha, Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden. Email: pernilla.wittung@chalmers.se and sandra.rocha@chalmers.se

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Unraveling amyloid formation paths of Parkinson's disease protein α-synuclein triggered by anionic vesicles

  • Juris Kiskis (a1), Istvan Horvath (a1), Pernilla Wittung-Stafshede (a1) and Sandra Rocha (a1)

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