Aarhus University Seal / Aarhus Universitets segl

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Standard

Identification of on- and off-pathway oligomers in amyloid fibril formation. / Dear, Alexander J.; Meisl, Georg; Saric, Andela; Michaels, Thomas C. T.; Kjaergaard, Magnus; Linse, Sara; Knowles, Tuomas P. J.

I: Chemical Science, Bind 11, Nr. 24, 06.2020, s. 6236-6247.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

Dear, AJ, Meisl, G, Saric, A, Michaels, TCT, Kjaergaard, M, Linse, S & Knowles, TPJ 2020, 'Identification of on- and off-pathway oligomers in amyloid fibril formation', Chemical Science, bind 11, nr. 24, s. 6236-6247. https://doi.org/10.1039/c9sc06501f

APA

Dear, A. J., Meisl, G., Saric, A., Michaels, T. C. T., Kjaergaard, M., Linse, S., & Knowles, T. P. J. (2020). Identification of on- and off-pathway oligomers in amyloid fibril formation. Chemical Science, 11(24), 6236-6247. https://doi.org/10.1039/c9sc06501f

CBE

Dear AJ, Meisl G, Saric A, Michaels TCT, Kjaergaard M, Linse S, Knowles TPJ. 2020. Identification of on- and off-pathway oligomers in amyloid fibril formation. Chemical Science. 11(24):6236-6247. https://doi.org/10.1039/c9sc06501f

MLA

Vancouver

Dear AJ, Meisl G, Saric A, Michaels TCT, Kjaergaard M, Linse S o.a. Identification of on- and off-pathway oligomers in amyloid fibril formation. Chemical Science. 2020 jun;11(24):6236-6247. https://doi.org/10.1039/c9sc06501f

Author

Dear, Alexander J. ; Meisl, Georg ; Saric, Andela ; Michaels, Thomas C. T. ; Kjaergaard, Magnus ; Linse, Sara ; Knowles, Tuomas P. J. / Identification of on- and off-pathway oligomers in amyloid fibril formation. I: Chemical Science. 2020 ; Bind 11, Nr. 24. s. 6236-6247.

Bibtex

@article{9d265008fc764856b5d2b5b84008fd87,
title = "Identification of on- and off-pathway oligomers in amyloid fibril formation",
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.",
keywords = "SINGLE-MOLECULE FLUORESCENCE, ALPHA-SYNUCLEIN OLIGOMERS, PHASE-SEPARATION, LAG PHASE, PROTEIN, AGGREGATION, MECHANISM, NUCLEATION, DIVERSITY, TOXICITY",
author = "Dear, {Alexander J.} and Georg Meisl and Andela Saric and Michaels, {Thomas C. T.} and Magnus Kjaergaard and Sara Linse and Knowles, {Tuomas P. J.}",
year = "2020",
month = jun,
doi = "10.1039/c9sc06501f",
language = "English",
volume = "11",
pages = "6236--6247",
journal = "Chemical Science",
issn = "2041-6520",
publisher = "royal society of chemistry",
number = "24",

}

RIS

TY - JOUR

T1 - Identification of on- and off-pathway oligomers in amyloid fibril formation

AU - Dear, Alexander J.

AU - Meisl, Georg

AU - Saric, Andela

AU - Michaels, Thomas C. T.

AU - Kjaergaard, Magnus

AU - Linse, Sara

AU - Knowles, Tuomas P. J.

PY - 2020/6

Y1 - 2020/6

N2 - 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.

AB - 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.

KW - SINGLE-MOLECULE FLUORESCENCE

KW - ALPHA-SYNUCLEIN OLIGOMERS

KW - PHASE-SEPARATION

KW - LAG PHASE

KW - PROTEIN

KW - AGGREGATION

KW - MECHANISM

KW - NUCLEATION

KW - DIVERSITY

KW - TOXICITY

U2 - 10.1039/c9sc06501f

DO - 10.1039/c9sc06501f

M3 - Journal article

C2 - 32953019

VL - 11

SP - 6236

EP - 6247

JO - Chemical Science

JF - Chemical Science

SN - 2041-6520

IS - 24

ER -