Cloutier2012 - Feedback motif for Parkinson's disease

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Cloutier2012 - Feedback motif for Parkinson's disease

This model is described in the article:

Cloutier M, Middleton R, Wellstead P.
IET Syst Biol 2012 Jun; 6(3): 86-93

Abstract:

Previous article on the integrative modelling of Parkinson's disease (PD) described a mathematical model with properties suggesting that PD pathogenesis is associated with a feedback-induced biochemical bistability. In this article, the authors show that the dynamics of the mathematical model can be extracted and distilled into an equivalent two-state feedback motif whose stability properties are controlled by multi-factorial combinations of risk factors and genetic mutations associated with PD. Based on this finding, the authors propose a principle for PD pathogenesis in the form of the switch-like transition of a bistable feedback process from 'healthy' homeostatic levels of reactive oxygen species and the protein ?-synuclein, to an alternative 'disease' state in which concentrations of both molecules are stable at the damagingly high-levels associated with PD. The bistability is analysed using the rate curves and steady-state response characteristics of the feedback motif. In particular, the authors show how a bifurcation in the feedback motif marks the pathogenic moment at which the 'healthy' state is lost and the 'disease' state is initiated. Further analysis shows how known risks (such as: age, toxins and genetic predisposition) modify the stability characteristics of the feedback motif in a way that is compatible with known features of PD, and which explain properties such as: multi-factorial causality, variability in susceptibility and severity, multi-timescale progression and the special cases of familial Parkinson's and Parkinsonian symptoms induced purely by toxic stress.

Stress of 2.6 obtained by optimization (parameter S1) was imposed between days 10 and 150 in order to reproduce the Figure.

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Format
SBML (L2V4)
Related Publication
  • Feedback motif for the pathogenesis of Parkinson's disease.
  • Cloutier M, Middleton R, Wellstead P
  • IET systems biology , 6/ 2012 , Volume 6 , pages: 86-93
  • GERAD and Department of Chemical Engineering, École Polytechnique de Montréal, Montréal, QC, Canada H3T 1J4. mathieu.cloutier@gerad.ca
  • Previous article on the integrative modelling of Parkinson's disease (PD) described a mathematical model with properties suggesting that PD pathogenesis is associated with a feedback-induced biochemical bistability. In this article, the authors show that the dynamics of the mathematical model can be extracted and distilled into an equivalent two-state feedback motif whose stability properties are controlled by multi-factorial combinations of risk factors and genetic mutations associated with PD. Based on this finding, the authors propose a principle for PD pathogenesis in the form of the switch-like transition of a bistable feedback process from 'healthy' homeostatic levels of reactive oxygen species and the protein α-synuclein, to an alternative 'disease' state in which concentrations of both molecules are stable at the damagingly high-levels associated with PD. The bistability is analysed using the rate curves and steady-state response characteristics of the feedback motif. In particular, the authors show how a bifurcation in the feedback motif marks the pathogenic moment at which the 'healthy' state is lost and the 'disease' state is initiated. Further analysis shows how known risks (such as: age, toxins and genetic predisposition) modify the stability characteristics of the feedback motif in a way that is compatible with known features of PD, and which explain properties such as: multi-factorial causality, variability in susceptibility and severity, multi-timescale progression and the special cases of familial Parkinson's and Parkinsonian symptoms induced purely by toxic stress.
Contributors
Audald Lloret i Villas

Metadata information

is
BioModels Database MODEL1410300000
BioModels Database BIOMD0000000558
isDescribedBy
PubMed 22757587
isDerivedFrom
PubMed 22757585
hasTaxon
Taxonomy Homo sapiens
isVersionOf
hasVersion
Human Disease Ontology Parkinson's disease
Curation status
Curated
  • Model originally submitted by : Audald Lloret i Villas
  • Submitted: Oct 30, 2014 1:18:01 PM
  • Last Modified: Apr 17, 2015 11:08:05 AM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Apr 17, 2015 11:08:05 AM
    • Submitted by: Audald Lloret i Villas
    • With comment: Current version of Cloutier2012 - Feedback motif for Parkinson's disease
  • Version: 1 public model Download this version
    • Submitted on: Oct 30, 2014 1:18:01 PM
    • Submitted by: Audald Lloret i Villas
    • With comment: Original import of Cloutier2012 - Feedback motif for Parkinson's disease
Curator's comment:
(added: 28 Nov 2014, 11:18:42, updated: 28 Nov 2014, 11:18:42)
Figure 1C of the reference publication has been reproduced here. Concentration dynamics of misfolded ?-synuclein (?SN) and Reactive Oxygen Spices (ROS) are plotted over 200 days. Stress of 2.6 obtained by optimization (parameter S1) was imposed between days 10 and 150 in order to reproduce the Figure. Reactions, parameters, rate equations and differential equations are found in Figure 1 and Table 1. The simulation was done using Copasi v4.14 (Build 89) and the plots were generated using Gnuplot. The Copasi file of the model with simulation settings can be downloaded from the below link: