Cloutier M, Middleton R, Wellstead P.
Feedback motif for the pathogenesis of Parkinson's disease.
IET Syst Biol 2012 Jun; 6(3): 86-93
GERAD and Department of Chemical Engineering, École Polytechnique de Montréal, Montréal, QC, Canada H3T 1J4. mathieu.cloutier@gerad.ca [more]

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.

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.