Dataset Information

Cloutier2012 - Feedback motif for Parkinson's disease

ABSTRACT: Cloutier2012 - Feedback motif for Parkinson's disease This model is described in the article: Feedback motif for the pathogenesis of Parkinson's disease. 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. This model is hosted on BioModels Database and identified by: BIOMD0000000558. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

DISEASE(S): Parkinson's Disease

SUBMITTER: Audald Lloret i Villas

PROVIDER: BIOMD0000000558 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000558?filename=BIOMD0000000558-biopax2.owl	Owl
	BIOMD0000000558?filename=BIOMD0000000558-biopax3.owl	Owl
	BIOMD0000000558?filename=BIOMD0000000558-matlab.m	Other
	BIOMD0000000558?filename=BIOMD0000000558-octave.m	Other
	BIOMD0000000558?filename=BIOMD0000000558.m	Other

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Feedback motif for the pathogenesis of Parkinson's disease.

Cloutier M M Middleton R R Wellstead P P

IET systems biology 20120601 3

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. ...[more]

PMID: 22757587

Publication: 1/2

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