Format

Send to

Choose Destination
See comment in PubMed Commons below
IET Syst Biol. 2012 Jun;6(3):86-93. doi: 10.1049/iet-syb.2011.0076.

Feedback motif for the pathogenesis of Parkinson's disease.

Author information

1
GERAD and Department of Chemical Engineering, École Polytechnique de Montréal, Montréal, QC, Canada H3T 1J4. mathieu.cloutier@gerad.ca

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.

PMID:
22757587
DOI:
10.1049/iet-syb.2011.0076
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Loading ...
    Support Center