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Structural characteristics and membrane interactions of tandem α-synuclein oligomers

Pre-fibrillar oligomers of α-synuclein are thought to be pathogenic molecules leading to neurotoxicity associated with Parkinson’s disease and other neurodegenerative disorders. However, small oligomers are difficult to isolate for study. To gain better insight into the properties of small α-synucle...

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Autores principales: Dong, Chunhua, Hoffmann, Marion, Li, Xi, Wang, Meijing, Garen, Craig R., Petersen, Nils O., Woodside, Michael T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928076/
https://www.ncbi.nlm.nih.gov/pubmed/29712958
http://dx.doi.org/10.1038/s41598-018-25133-0
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author Dong, Chunhua
Hoffmann, Marion
Li, Xi
Wang, Meijing
Garen, Craig R.
Petersen, Nils O.
Woodside, Michael T.
author_facet Dong, Chunhua
Hoffmann, Marion
Li, Xi
Wang, Meijing
Garen, Craig R.
Petersen, Nils O.
Woodside, Michael T.
author_sort Dong, Chunhua
collection PubMed
description Pre-fibrillar oligomers of α-synuclein are thought to be pathogenic molecules leading to neurotoxicity associated with Parkinson’s disease and other neurodegenerative disorders. However, small oligomers are difficult to isolate for study. To gain better insight into the properties of small α-synuclein oligomers, we investigated engineered oligomers of specific size (dimers, tetramers, and octamers) linked head-to-tail in tandem, comparing the behavior of the oligomers to monomeric α-synuclein. All oligomeric constructs remained largely disordered in solution, as determined from dynamic light scattering and size-exclusion chromatography. Electron microscopy revealed that each construct could aggregate to form fibrils similar to those formed by monomeric α-synuclein. The interactions with large unilamellar vesicles (LUVs) composed of negatively-charged lipids differed depending on size, with smaller oligomers forming more extensive helical structure as determined by CD spectroscopy. Monitoring the influx of a fluorescence bleaching agent into vesicles showed that larger oligomers were somewhat more effective at degrading vesicular integrity and inducing membrane permeabilization.
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spelling pubmed-59280762018-05-07 Structural characteristics and membrane interactions of tandem α-synuclein oligomers Dong, Chunhua Hoffmann, Marion Li, Xi Wang, Meijing Garen, Craig R. Petersen, Nils O. Woodside, Michael T. Sci Rep Article Pre-fibrillar oligomers of α-synuclein are thought to be pathogenic molecules leading to neurotoxicity associated with Parkinson’s disease and other neurodegenerative disorders. However, small oligomers are difficult to isolate for study. To gain better insight into the properties of small α-synuclein oligomers, we investigated engineered oligomers of specific size (dimers, tetramers, and octamers) linked head-to-tail in tandem, comparing the behavior of the oligomers to monomeric α-synuclein. All oligomeric constructs remained largely disordered in solution, as determined from dynamic light scattering and size-exclusion chromatography. Electron microscopy revealed that each construct could aggregate to form fibrils similar to those formed by monomeric α-synuclein. The interactions with large unilamellar vesicles (LUVs) composed of negatively-charged lipids differed depending on size, with smaller oligomers forming more extensive helical structure as determined by CD spectroscopy. Monitoring the influx of a fluorescence bleaching agent into vesicles showed that larger oligomers were somewhat more effective at degrading vesicular integrity and inducing membrane permeabilization. Nature Publishing Group UK 2018-04-30 /pmc/articles/PMC5928076/ /pubmed/29712958 http://dx.doi.org/10.1038/s41598-018-25133-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Dong, Chunhua
Hoffmann, Marion
Li, Xi
Wang, Meijing
Garen, Craig R.
Petersen, Nils O.
Woodside, Michael T.
Structural characteristics and membrane interactions of tandem α-synuclein oligomers
title Structural characteristics and membrane interactions of tandem α-synuclein oligomers
title_full Structural characteristics and membrane interactions of tandem α-synuclein oligomers
title_fullStr Structural characteristics and membrane interactions of tandem α-synuclein oligomers
title_full_unstemmed Structural characteristics and membrane interactions of tandem α-synuclein oligomers
title_short Structural characteristics and membrane interactions of tandem α-synuclein oligomers
title_sort structural characteristics and membrane interactions of tandem α-synuclein oligomers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928076/
https://www.ncbi.nlm.nih.gov/pubmed/29712958
http://dx.doi.org/10.1038/s41598-018-25133-0
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