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Issue 24, 2020
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Identification of on- and off-pathway oligomers in amyloid fibril formation

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Abstract

The misfolding and aberrant aggregation of proteins into fibrillar structures is a key factor in some of the most prevalent human diseases, including diabetes and dementia. Low molecular weight oligomers are thought to be a central factor in the pathology of these diseases, as well as critical intermediates in the fibril formation process, and as such have received much recent attention. Moreover, on-pathway oligomeric intermediates are potential targets for therapeutic strategies aimed at interrupting the fibril formation process. However, a consistent framework for distinguishing on-pathway from off-pathway oligomers has hitherto been lacking and, in particular, no consensus definition of on- and off-pathway oligomers is available. In this paper, we argue that a non-binary definition of oligomers' contribution to fibril-forming pathways may be more informative and we suggest a quantitative framework, in which each oligomeric species is assigned a value between 0 and 1 describing its relative contribution to the formation of fibrils. First, we clarify the distinction between oligomers and fibrils, and then we use the formalism of reaction networks to develop a general definition for on-pathway oligomers, that yields meaningful classifications in the context of amyloid formation. By applying these concepts to Monte Carlo simulations of a minimal aggregating system, and by revisiting several previous studies of amyloid oligomers in light of our new framework, we demonstrate how to perform these classifications in practice. For each oligomeric species we obtain the degree to which it is on-pathway, highlighting the most effective pharmaceutical targets for the inhibition of amyloid fibril formation.

Graphical abstract: Identification of on- and off-pathway oligomers in amyloid fibril formation

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Article information


Submitted
23 Dec 2019
Accepted
26 May 2020
First published
08 Jun 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 6236-6247
Article type
Edge Article

Identification of on- and off-pathway oligomers in amyloid fibril formation

A. J. Dear, G. Meisl, A. Šarić, T. C. T. Michaels, M. Kjaergaard, S. Linse and T. P. J. Knowles, Chem. Sci., 2020, 11, 6236 DOI: 10.1039/C9SC06501F

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