Feedback motif for the pathogenesis of Parkinson's disease.
Identifieur interne : 001232 ( Main/Exploration ); précédent : 001231; suivant : 001233Feedback motif for the pathogenesis of Parkinson's disease.
Auteurs : M. Cloutier [Canada] ; R. Middleton ; P. WellsteadSource :
- IET systems biology [ 1751-8849 ] ; 2012.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Oxygen, Reactive Oxygen Species, alpha-Synuclein.
- metabolism : Aging, Brain, Parkinson Disease.
- Computer Simulation, Feedback, Physiological, Humans, Models, Biological, Oxidation-Reduction, Oxygen Consumption.
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 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.
DOI: 10.1049/iet-syb.2011.0076
PubMed: 22757587
Affiliations:
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Le document en format XML
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Cloutier</name><affiliation wicri:level="1"><nlm:affiliation>GERAD and Department of Chemical Engineering, École Polytechnique de Montréal, Montréal, QC, Canada H3T 1J4. mathieu.cloutier@gerad.ca</nlm:affiliation><country>Canada</country><wicri:regionArea>GERAD and Department of Chemical Engineering, École Polytechnique de Montréal, Montréal, QC</wicri:regionArea><wicri:noRegion>QC</wicri:noRegion></affiliation></author><author><name sortKey="Middleton, R" sort="Middleton, R" uniqKey="Middleton R" first="R" last="Middleton">R. Middleton</name></author><author><name sortKey="Wellstead, P" sort="Wellstead, P" uniqKey="Wellstead P" first="P" last="Wellstead">P. Wellstead</name></author></analytic><series><title level="j">IET systems biology</title><idno type="ISSN">1751-8849</idno><imprint><date when="2012" type="published">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aging (metabolism)</term><term>Brain (metabolism)</term><term>Computer Simulation</term><term>Feedback, Physiological</term><term>Humans</term><term>Models, Biological</term><term>Oxidation-Reduction</term><term>Oxygen (metabolism)</term><term>Oxygen Consumption</term><term>Parkinson Disease (metabolism)</term><term>Reactive Oxygen Species (metabolism)</term><term>alpha-Synuclein (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Oxygen</term><term>Reactive Oxygen Species</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Aging</term><term>Brain</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Computer Simulation</term><term>Feedback, Physiological</term><term>Humans</term><term>Models, Biological</term><term>Oxidation-Reduction</term><term>Oxygen Consumption</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Middleton, R" sort="Middleton, R" uniqKey="Middleton R" first="R" last="Middleton">R. Middleton</name><name sortKey="Wellstead, P" sort="Wellstead, P" uniqKey="Wellstead P" first="P" last="Wellstead">P. Wellstead</name></noCountry><country name="Canada"><noRegion><name sortKey="Cloutier, M" sort="Cloutier, M" uniqKey="Cloutier M" first="M" last="Cloutier">M. 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