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

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Dear, Alexander J.Lund University,University of Cambridge (author)

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

Article/chapterEnglish2020

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2020
Royal Society of Chemistry (RSC),2020
12 s.

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LIBRIS-ID:oai:lup.lub.lu.se:37473179-9a77-4657-b7c5-72f08ac8da33
https://lup.lub.lu.se/record/37473179-9a77-4657-b7c5-72f08ac8da33URI
https://doi.org/10.1039/c9sc06501fDOI

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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. This journal is

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Meisl, GeorgUniversity of Cambridge (author)
Šarić, AnđelaUniversity College London (author)
Michaels, Thomas C.T.University of Cambridge (author)
Kjaergaard, MagnusAarhus University (author)
Linse, SaraLund University,Lunds universitet,NanoLund: Centre for Nanoscience,Annan verksamhet, LTH,Lunds Tekniska Högskola,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Other operations, LTH,Faculty of Engineering, LTH,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH(Swepub:lu)fkm2-sli (author)
Knowles, Tuomas P.J.University of Cambridge (author)
Lund UniversityUniversity of Cambridge (creator_code:org_t)

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In:Chemical Science: Royal Society of Chemistry (RSC)11:24, s. 6236-62472041-65202041-6539

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