Kinetic diversity of amyloid oligomers.

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 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.

authors

Dear AJ,Michaels TCT,Meisl G,Klenerman D,Wu S,Perrett S,Linse S,Dobson CM,Knowles TPJ

doi

10.1073/pnas.1922267117

subject

Has Abstract

pub_date

2020-06-02 00:00:00

pages

12087-12094

issue

22

eissn

0027-8424

issn

1091-6490

pii

1922267117

journal_volume

117

pub_type

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