Kinetic diversity of amyloid oligomers
(2020) In Proceedings of the National Academy of Sciences of the United States of America 117(22).- Abstract
The spontaneous assembly of proteins into amyloid fibrils is a phenomenon central to many increasingly common and currently incurable human disorders, including Alzheimer's and Parkinson's diseases. Oligomeric species form transiently during this process and not only act as essential intermediates in the assembly of new filaments but also represent major pathogenic agents in these diseases. While amyloid fibrils possess a common, defining set of physicochemical features, oligomers, by contrast, appear much more diverse, and their commonalities and differences have hitherto remained largely unexplored. Here, we use the framework of chemical kinetics to investigate their dynamical properties. By fitting experimental data for several... (More)
The spontaneous assembly of proteins into amyloid fibrils is a phenomenon central to many increasingly common and currently incurable human disorders, including Alzheimer's and Parkinson's diseases. Oligomeric species form transiently during this process and not only act as essential intermediates in the assembly of new filaments but also represent major pathogenic agents in these diseases. While amyloid fibrils possess a common, defining set of physicochemical features, oligomers, by contrast, appear much more diverse, and their commonalities and differences have hitherto remained largely unexplored. Here, we use the framework of chemical kinetics to investigate their dynamical properties. By fitting experimental data for several unrelated amyloidogenic systems to newly derived mechanistic models, we find that oligomers present with a remarkably wide range of kinetic and thermodynamic stabilities but that they possess two properties that are generic: they are overwhelmingly nonfibrillar, and they predominantly dissociate back to monomers rather than maturing into fibrillar species. These discoveries change our understanding of the relationship between amyloid oligomers and amyloid fibrils and have important implications for the nature of their cellular toxicity.
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- author
- Dear, Alexander J. ; Michaels, Thomas C.T. ; Meisl, Georg ; Klenerman, David ; Wu, Si ; Perrett, Sarah ; Linse, Sara LU ; Dobson, Christopher M. and Knowles, Tuomas P.J.
- organization
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alzheimer's, Amyloid, Kinetics, Modeling, Oligomers
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 117
- issue
- 22
- article number
- pnas1922267117
- publisher
- National Academy of Sciences
- external identifiers
-
- scopus:85085904348
- pmid:32414930
- ISSN
- 0027-8424
- DOI
- 10.1073/pnas.1922267117
- language
- English
- LU publication?
- yes
- id
- 25acf96a-1d74-4d55-a7a9-b2e0ce73db0e
- date added to LUP
- 2020-12-18 13:16:26
- date last changed
- 2024-04-17 21:23:50
@article{25acf96a-1d74-4d55-a7a9-b2e0ce73db0e,
abstract = {{<p>The spontaneous assembly of proteins into amyloid fibrils is a phenomenon central to many increasingly common and currently incurable human disorders, including Alzheimer's and Parkinson's diseases. Oligomeric species form transiently during this process and not only act as essential intermediates in the assembly of new filaments but also represent major pathogenic agents in these diseases. While amyloid fibrils possess a common, defining set of physicochemical features, oligomers, by contrast, appear much more diverse, and their commonalities and differences have hitherto remained largely unexplored. Here, we use the framework of chemical kinetics to investigate their dynamical properties. By fitting experimental data for several unrelated amyloidogenic systems to newly derived mechanistic models, we find that oligomers present with a remarkably wide range of kinetic and thermodynamic stabilities but that they possess two properties that are generic: they are overwhelmingly nonfibrillar, and they predominantly dissociate back to monomers rather than maturing into fibrillar species. These discoveries change our understanding of the relationship between amyloid oligomers and amyloid fibrils and have important implications for the nature of their cellular toxicity.</p>}},
author = {{Dear, Alexander J. and Michaels, Thomas C.T. and Meisl, Georg and Klenerman, David and Wu, Si and Perrett, Sarah and Linse, Sara and Dobson, Christopher M. and Knowles, Tuomas P.J.}},
issn = {{0027-8424}},
keywords = {{Alzheimer's; Amyloid; Kinetics; Modeling; Oligomers}},
language = {{eng}},
number = {{22}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Kinetic diversity of amyloid oligomers}},
url = {{http://dx.doi.org/10.1073/pnas.1922267117}},
doi = {{10.1073/pnas.1922267117}},
volume = {{117}},
year = {{2020}},
}