GERAD and Department of Chemical Engineering, École Polytechnique de Montréal, Montréal, QC, Canada H3T 1J4.
IET Syst Biol. 2012 Jun;6(3):86-93. doi: 10.1049/iet-syb.2011.0076.
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.
前文介绍了帕金森病（PD）的综合建模，提出了一个具有特征的数学模型，表明 PD 的发病机制与反馈诱导的生化双稳态有关。本文中，作者展示了数学模型的动力学可以被提取并简化为等效的双态反馈模式，其稳定性特性由与 PD 相关的多种危险因素和基因突变的多因素组合控制。基于这一发现，作者提出了一个 PD 发病机制的原则，即双稳态反馈过程从“健康”的活性氧和蛋白质 α-突触核蛋白的稳态水平到另一个“疾病”状态的开关式转变，在这种状态下，两种分子的浓度都稳定在与 PD 相关的高损伤水平。双稳态通过反馈模式的速率曲线和稳态响应特性进行分析。特别是，作者展示了反馈模式中的分岔如何标记发病时刻，即“健康”状态丧失和“疾病”状态开始的时刻。进一步的分析表明，已知的风险因素（如年龄、毒素和遗传易感性）如何以与 PD 的已知特征兼容的方式改变反馈模式的稳定性特征，并解释了多因素因果关系、易感性和严重程度的可变性、多时间尺度进展以及纯粹由毒性应激引起的家族性帕金森病和帕金森症状的特殊情况等特性。
