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Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism

BACKGROUND: The question of how the aggregation of the neuronal protein α-synuclein contributes to neuronal toxicity in Parkinson's disease has been the subject of intensive research over the past decade. Recently, attention has shifted from the amyloid fibrils to soluble oligomeric intermediat...

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Detalles Bibliográficos
Autores principales: van Rooijen, Bart D., Claessens, Mireille M. A. E., Subramaniam, Vinod
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001441/
https://www.ncbi.nlm.nih.gov/pubmed/21179192
http://dx.doi.org/10.1371/journal.pone.0014292
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author van Rooijen, Bart D.
Claessens, Mireille M. A. E.
Subramaniam, Vinod
author_facet van Rooijen, Bart D.
Claessens, Mireille M. A. E.
Subramaniam, Vinod
author_sort van Rooijen, Bart D.
collection PubMed
description BACKGROUND: The question of how the aggregation of the neuronal protein α-synuclein contributes to neuronal toxicity in Parkinson's disease has been the subject of intensive research over the past decade. Recently, attention has shifted from the amyloid fibrils to soluble oligomeric intermediates in the α-synuclein aggregation process. These oligomers are hypothesized to be cytotoxic and to permeabilize cellular membranes, possibly by forming pore-like complexes in the bilayer. Although the subject of α-synuclein oligomer-membrane interactions has attracted much attention, there is only limited evidence that supports the pore formation by α-synuclein oligomers. In addition the existing data are contradictory. METHODOLOGY/PRINCIPAL FINDINGS: Here we have studied the mechanism of lipid bilayer disruption by a well-characterized α-synuclein oligomer species in detail using a number of in vitro bilayer systems and assays. Dye efflux from vesicles induced by oligomeric α-synuclein was found to be a fast all-or-none process. Individual vesicles swiftly lose their contents but overall vesicle morphology remains unaltered. A newly developed assay based on a dextran-coupled dye showed that non-equilibrium processes dominate the disruption of the vesicles. The membrane is highly permeable to solute influx directly after oligomer addition, after which membrane integrity is partly restored. The permeabilization of the membrane is possibly related to the intrinsic instability of the bilayer. Vesicles composed of negatively charged lipids, which are generally used for measuring α-synuclein-lipid interactions, were unstable to protein adsorption in general. CONCLUSIONS/SIGNIFICANCE: The dye efflux from negatively charged vesicles upon addition of α-synuclein has been hypothesized to occur through the formation of oligomeric membrane pores. However, our results show that the dye efflux characteristics are consistent with bilayer defects caused by membrane instability. These data shed new insights into potential mechanisms of toxicity of oligomeric α-synuclein species.
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spelling pubmed-30014412010-12-21 Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism van Rooijen, Bart D. Claessens, Mireille M. A. E. Subramaniam, Vinod PLoS One Research Article BACKGROUND: The question of how the aggregation of the neuronal protein α-synuclein contributes to neuronal toxicity in Parkinson's disease has been the subject of intensive research over the past decade. Recently, attention has shifted from the amyloid fibrils to soluble oligomeric intermediates in the α-synuclein aggregation process. These oligomers are hypothesized to be cytotoxic and to permeabilize cellular membranes, possibly by forming pore-like complexes in the bilayer. Although the subject of α-synuclein oligomer-membrane interactions has attracted much attention, there is only limited evidence that supports the pore formation by α-synuclein oligomers. In addition the existing data are contradictory. METHODOLOGY/PRINCIPAL FINDINGS: Here we have studied the mechanism of lipid bilayer disruption by a well-characterized α-synuclein oligomer species in detail using a number of in vitro bilayer systems and assays. Dye efflux from vesicles induced by oligomeric α-synuclein was found to be a fast all-or-none process. Individual vesicles swiftly lose their contents but overall vesicle morphology remains unaltered. A newly developed assay based on a dextran-coupled dye showed that non-equilibrium processes dominate the disruption of the vesicles. The membrane is highly permeable to solute influx directly after oligomer addition, after which membrane integrity is partly restored. The permeabilization of the membrane is possibly related to the intrinsic instability of the bilayer. Vesicles composed of negatively charged lipids, which are generally used for measuring α-synuclein-lipid interactions, were unstable to protein adsorption in general. CONCLUSIONS/SIGNIFICANCE: The dye efflux from negatively charged vesicles upon addition of α-synuclein has been hypothesized to occur through the formation of oligomeric membrane pores. However, our results show that the dye efflux characteristics are consistent with bilayer defects caused by membrane instability. These data shed new insights into potential mechanisms of toxicity of oligomeric α-synuclein species. Public Library of Science 2010-12-13 /pmc/articles/PMC3001441/ /pubmed/21179192 http://dx.doi.org/10.1371/journal.pone.0014292 Text en van Rooijen et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
van Rooijen, Bart D.
Claessens, Mireille M. A. E.
Subramaniam, Vinod
Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism
title Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism
title_full Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism
title_fullStr Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism
title_full_unstemmed Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism
title_short Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism
title_sort membrane permeabilization by oligomeric α-synuclein: in search of the mechanism
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001441/
https://www.ncbi.nlm.nih.gov/pubmed/21179192
http://dx.doi.org/10.1371/journal.pone.0014292
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