Issue |
ESAIM: ProcS
Volume 45, September 2014
Congrès SMAI 2013
|
|
---|---|---|
Page(s) | 189 - 198 | |
DOI | https://doi.org/10.1051/proc/201445019 | |
Published online | 13 November 2014 |
Modelling and analysis of protein aggregation - Competing pathways in prion (PrP) polymerisation*
1 Inria, Paris-Rocquencourt, Domaine de
Voluceau, BP105, 78153 Le Chesnay, France; LJLL, Laboratoire Jacques-Louis Lions,
Pierre et Marie Curie University, Boite courrier 187, 75252
Paris Cedex 05,
France
2 Inria; LJLL; INRA,
VIM, Domaine de Vilvert,
78352
Jouy-en-Josas cedex,
France
Protein aggregation leading to the formation of amyloid fibrils is involved in several neurodegenerative diseases such as prion diseases. To clarify how these fibrils are able to incorporate additional units, prion fibril aggregation and disaggregation kinetics were experimentally studied using Static Light Scattering (SLS). Values that are functions of ∑i ≥ 1i2 Ci, with ci being the concentration of fibrils of size i, were then measured as a function of time. An initial model, adapted from the Becker-Döring system that considers all fibrils to react similarly is not able to reproduce the observed in vitro behaviour. Our second model involves an additional compartment of fibrils unable to incorporate more prion units. This model leads to kinetic coefficients which are biologically plausible and correctly simulates the first experimental steps for prion aggregation.
Résumé
L’agrégation des protéines conduisant à la formation de fibres amyloïdes est impliquée dans plusieurs maladies neurodégénératives telles que les maladies à prion. Pour clarifier la manière dont les fibres de prion incorporent des unités supplémentaires, les cinétiques d’agrégation et de désagrégation des fibres ont été étudiées expérimentalement (par SLS, “Static Light Diffusion“). Ainsi des valeurs fonction de ∑i ≥ 1i2 Ci avec ci la concentration en fibres de taille i ont été obtenues en fonction du temps. Un premier modèle, adapté du système de Becker-Döring, qui considère que la totalité des fibres réagit de manière similaire ne permet pas de reproduire le comportement observé in vitro. Notre deuxième modèle met en jeu un compartiment additionnel de fibres incapables d’incorporer davantage d’unités de PrP. Celui-ci aboutit à des coefficients cinétiques biologiquement plausibles et simule correctement les premières étapes expérimentales de l’agrégation de prions.
The authors would like to warmly thank the head of this project, Marie Doumic-Jauffret (INRIA), for her major contribution to this work and Human Rezaei, Davy Martin (INRA) and Joan Torrent Y Mas (INSERM) for initiating this topic, the experimental part and discussions. This research was supported by the ERC Starting Grant SKIPPERAD (fully for S. Prigent and partially for W. Haffaf).
© EDP Sciences, SMAI 2014
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