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Kinetic diversity of amyloid oligomers

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. (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
; ; ; ; ; ; ; and
organization
publishing date
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 Acad Sciences
external identifiers
  • pmid:32414930
  • scopus:85085904348
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
2021-02-17 05:54:31
@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},
  language     = {eng},
  number       = {22},
  publisher    = {National Acad 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},
}