title: Feedback motif for the pathogenesis of Parkinson's disease.
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.
authors: GERAD and Department of Chemical Engineering, École Polytechnique de Montréal, Montréal, QC, Canada H3T 1J4. mathieu.cloutier@gerad.ca
authors: M
authors: M
authors: Cloutier
authors: R
authors: R
authors: Middleton
authors: P
authors: P
authors: Wellstead
mesh_terms: D000375:Aging / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D003198:Computer Simulation; D025461:Feedback, Physiological; D006801:Humans; D008954:Models, Biological; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D010300:Parkinson Disease / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D010100:Oxygen