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

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

Authors :
Dear AJ
Meisl G
Šarić A
Michaels TCT
Kjaergaard M
Linse S
Knowles TPJ
Source :
Chemical science [Chem Sci] 2020 Jun 08; Vol. 11 (24), pp. 6236-6247. Date of Electronic Publication: 2020 Jun 08 (Print Publication: 2020).
Publication Year :
2020

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.<br /> (This journal is © The Royal Society of Chemistry 2020.)

Details

Language :
English
ISSN :
2041-6520
Volume :
11
Issue :
24
Database :
MEDLINE
Journal :
Chemical science
Publication Type :
Academic Journal
Accession number :
32953019
Full Text :
https://doi.org/10.1039/c9sc06501f