An efficient kinetic model for assemblies of amyloid fibrils and its application to polyglutamine aggregation.

Stephanie Prigent 1 Annabelle Ballesta 2, 3 Frédérique Charles 4 Natacha Lenuzza 5 Pierre Gabriel 6, 7 Léon Matar Tine 8 Human Rezaei 1 Marie Doumic 3, 4
3 BANG - Nonlinear Analysis for Biology and Geophysical flows
LJLL - Laboratoire Jacques-Louis Lions, Inria Paris-Rocquencourt
6 BEAGLE - Artificial Evolution and Computational Biology
LIRIS - Laboratoire d'InfoRmatique en Image et Systèmes d'information, Inria Grenoble - Rhône-Alpes, LBBE - Laboratoire de Biométrie et Biologie Evolutive, CarMeN - Laboratoire de recherche en cardiovasculaire, métabolisme, diabétologie et nutrition
Abstract : Protein polymerization consists in the aggregation of single monomers into polymers that may fragment. Fibrils assembly is a key process in amyloid diseases. Up to now, protein aggregation was commonly mathematically simulated by a polymer size-structured ordinary differential equations (ODE) system, which is infinite by definition and therefore leads to high computational costs. Moreover, this Ordinary Differential Equation-based modeling approach implies biological assumptions that may be difficult to justify in the general case. For example, whereas several ordinary differential equation models use the assumption that polymerization would occur at a constant rate independently of polymer size, it cannot be applied to certain protein aggregation mechanisms. Here, we propose a novel and efficient analytical method, capable of modelling and simulating amyloid aggregation processes. This alternative approach consists of an integro-Partial Differential Equation (PDE) model of coalescence-fragmentation type that was mathematically derived from the infinite differential system by asymptotic analysis. To illustrate the efficiency of our approach, we applied it to aggregation experiments on polyglutamine polymers that are involved in Huntington's disease. Our model demonstrates the existence of a monomeric structural intermediate [Formula: see text] acting as a nucleus and deriving from a non polymerizing monomer ([Formula: see text]). Furthermore, we compared our model to previously published works carried out in different contexts and proved its accuracy to describe other amyloid aggregation processes.
Type de document :
Article dans une revue
PLoS ONE, Public Library of Science, 2012, 7 (11), pp.e43273. <10.1371/journal.pone.0043273>
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Contributeur : Marie Doumic <>
Soumis le : vendredi 18 janvier 2013 - 15:52:07
Dernière modification le : vendredi 17 février 2017 - 14:29:28

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Stephanie Prigent, Annabelle Ballesta, Frédérique Charles, Natacha Lenuzza, Pierre Gabriel, et al.. An efficient kinetic model for assemblies of amyloid fibrils and its application to polyglutamine aggregation.. PLoS ONE, Public Library of Science, 2012, 7 (11), pp.e43273. <10.1371/journal.pone.0043273>. <hal-00778052>

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