An Efficient Kinetic Model for Assemblies of Amyloid Fibrils and Its Application to Polyglutamine Aggregation 英文参考文献.docVIP

AnEfficientKineticModelforAssembliesofAmyloid FibrilsandItsApplicationtoPolyglutamineAggregation Ste′phaniePrigent1,AnnabelleBallesta2,Fre′de′riqueCharles3,NatachaLenuzza4,PierreGabriel5, Le′onMatarTine6,HumanRezaei1,MarieDoumic2* 1Institut National de Recherche Agronomique, Jouy-en-Josas, France, 2Institut National de Recherche en Informatique et Automatique, Rocquencourt, France, 3Universite′ Pierre et Marie Curie, Paris, France, 4Commissariat a` l’Energie Atomique, Gif-sur-Yvette, France, 5Institut National de Recherche en Informatique et AutomatiqueRho?nes-Alpes,Lyon,France,6Universite′ GastonBerger,Saint-Louis,Se′ne′gal Abstract Proteinpolymerizationconsistsintheaggregationofsinglemonomersintopolymersthatmayfragment.Fibrilsassemblyis akeyprocessinamyloiddiseases.Uptonow,proteinaggregationwascommonlymathematicallysimulatedbyapolymer 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 equationmodelsusetheassumptionthatpolymerizationwouldoccurataconstantrateindependentlyofpolymersize,it cannotbeappliedtocertainproteinaggregationmechanisms.Here,weproposeanovelandefficientanalyticalmethod, capableofmodellingandsimulatingamyloidaggregationprocesses.Thisalternativeapproachconsistsofanintegro-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 experimentsonpolyglutaminepolymersthatareinvolvedinHuntington’sdisease.Ourmodeldemonstratestheexistence of a monomeric structural intermediate ~c1 acting as a nucleus and deriving from a non polymerizing monomer (c1). Furthermore, we compared