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Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts
Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known about how differences in α-synuclein aggregate structure affect disease phenotype. Here, we amplified α-synuclein...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893031/ https://www.ncbi.nlm.nih.gov/pubmed/31797870 http://dx.doi.org/10.1038/s41467-019-13564-w |
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author | Strohäker, Timo Jung, Byung Chul Liou, Shu-Hao Fernandez, Claudio O. Riedel, Dietmar Becker, Stefan Halliday, Glenda M. Bennati, Marina Kim, Woojin S. Lee, Seung-Jae Zweckstetter, Markus |
author_facet | Strohäker, Timo Jung, Byung Chul Liou, Shu-Hao Fernandez, Claudio O. Riedel, Dietmar Becker, Stefan Halliday, Glenda M. Bennati, Marina Kim, Woojin S. Lee, Seung-Jae Zweckstetter, Markus |
author_sort | Strohäker, Timo |
collection | PubMed |
description | Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known about how differences in α-synuclein aggregate structure affect disease phenotype. Here, we amplified α-synuclein aggregates from PD and MSA brain extracts and analyzed the conformational properties using fluorescent probes, NMR spectroscopy and electron paramagnetic resonance. We also generated and analyzed several in vitro α-synuclein polymorphs. We found that brain-derived α-synuclein fibrils were structurally different to all of the in vitro polymorphs analyzed. Importantly, there was a greater structural heterogeneity among α-synuclein fibrils from the PD brain compared to those from the MSA brain, possibly reflecting on the greater variability of disease phenotypes evident in PD. Our findings have significant ramifications for the use of non-brain-derived α-synuclein fibrils in PD and MSA studies, and raise important questions regarding the one disease-one strain hypothesis in the study of α-synucleinopathies. |
format | Online Article Text |
id | pubmed-6893031 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68930312019-12-06 Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts Strohäker, Timo Jung, Byung Chul Liou, Shu-Hao Fernandez, Claudio O. Riedel, Dietmar Becker, Stefan Halliday, Glenda M. Bennati, Marina Kim, Woojin S. Lee, Seung-Jae Zweckstetter, Markus Nat Commun Article Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known about how differences in α-synuclein aggregate structure affect disease phenotype. Here, we amplified α-synuclein aggregates from PD and MSA brain extracts and analyzed the conformational properties using fluorescent probes, NMR spectroscopy and electron paramagnetic resonance. We also generated and analyzed several in vitro α-synuclein polymorphs. We found that brain-derived α-synuclein fibrils were structurally different to all of the in vitro polymorphs analyzed. Importantly, there was a greater structural heterogeneity among α-synuclein fibrils from the PD brain compared to those from the MSA brain, possibly reflecting on the greater variability of disease phenotypes evident in PD. Our findings have significant ramifications for the use of non-brain-derived α-synuclein fibrils in PD and MSA studies, and raise important questions regarding the one disease-one strain hypothesis in the study of α-synucleinopathies. Nature Publishing Group UK 2019-12-04 /pmc/articles/PMC6893031/ /pubmed/31797870 http://dx.doi.org/10.1038/s41467-019-13564-w Text en © The Author(s) 2019 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 Strohäker, Timo Jung, Byung Chul Liou, Shu-Hao Fernandez, Claudio O. Riedel, Dietmar Becker, Stefan Halliday, Glenda M. Bennati, Marina Kim, Woojin S. Lee, Seung-Jae Zweckstetter, Markus Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts |
title | Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts |
title_full | Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts |
title_fullStr | Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts |
title_full_unstemmed | Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts |
title_short | Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts |
title_sort | structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893031/ https://www.ncbi.nlm.nih.gov/pubmed/31797870 http://dx.doi.org/10.1038/s41467-019-13564-w |
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