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BIOMD0000000558 - Cloutier2012 - Feedback motif for Parkinson's disease

 

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Reference Publication
Publication ID: 22757587
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]
Model
Original Model: BIOMD0000000558.origin
Submitter: Audald Lloret i Villas
Submission ID: MODEL1410300000
Submission Date: 30 Oct 2014 13:18:01 UTC
Last Modification Date: 17 Apr 2015 11:08:05 UTC
Creation Date: 26 Nov 2014 11:29:00 UTC
Encoders:  Audald Lloret i Villas
set #1
bqbiol:hasVersion Human Disease Ontology Parkinson's disease
set #2
bqbiol:isVersionOf Gene Ontology inclusion body assembly
Gene Ontology response to reactive oxygen species
set #3
bqbiol:hasTaxon Taxonomy Homo sapiens
set #4
bqmodel:isDerivedFrom PubMed 22757585
Notes
Cloutier2012 - Feedback motif for Parkinson's disease

This model is described in the article:

Cloutier M, Middleton R, Wellstead P.
IET Syst Biol 2012 Jun; 6(3): 86-93

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 ?-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.

Model
Publication ID: 22757587 Submission Date: 30 Oct 2014 13:18:01 UTC Last Modification Date: 17 Apr 2015 11:08:05 UTC Creation Date: 26 Nov 2014 11:29:00 UTC
Mathematical expressions
Reactions
ROS 1 ROS 2 aSyn 1 aSyn 2
Rules
Assignment Rule (variable: S1)      
Physical entities
Compartments Species
Neuron ROS alpha-syn  
Global parameters
k1 k2 k3 k4
dalphasyn kalphasyn S1 S2-4
Reactions (4)
 
 ROS 1  → [ROS];   {alpha-syn} , {alpha-syn}
 
 ROS 2 [ROS] → ;   {ROS}
 
 aSyn 1  → [alpha-syn];   {ROS} , {ROS}
 
 aSyn 2 [alpha-syn] → ;   {alpha-syn}
 
Rules (1)
 
 Assignment Rule (name: S1) S1 = piecewise(2.6, (time > 10) && (time < 150), 0)
 
Functions (3)
 
 V2-4 lambda(k, S, Sx, k*S*Sx)
 
 V3 lambda(k, S, Sx, k*S*Sx)
 
 V1 lambda(k1, Sx, d, S, k2, k1*(1+Sx+d*(S/k2)^4/(1+(S/k2)^4)))
 
 Neuron Spatial dimensions: 3.0  Compartment size: 1.0
 
 ROS
Compartment: Neuron
Initial concentration: 1.0
 
 alpha-syn
Compartment: Neuron
Initial concentration: 1.0
 
Global Parameters (8)
 
 k1
Value: 17280.0
Constant
 
 k2
Value: 17280.0
Constant
 
 k3
Value: 0.168
Constant
 
 k4
Value: 0.168
Constant
 
 dalphasyn
Value: 15.0
Constant
 
 kalphasyn
Value: 8.5
Constant
 
  S1  
 
 S2-4
Value: 1.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000558

Curator's comment: (updated: 28 Nov 2014 11:18:42 GMT)

Figure 1C of the reference publication has been reproduced here. Concentration dynamics of misfolded ?-synuclein (?SN) and Reactive Oxygen Spices (ROS) are plotted over 200 days.
Stress of 2.6 obtained by optimization (parameter S1) was imposed between days 10 and 150 in order to reproduce the Figure.

Reactions, parameters, rate equations and differential equations are found in Figure 1 and Table 1.

The simulation was done using Copasi v4.14 (Build 89) and the plots were generated using Gnuplot. The Copasi file of the model with simulation settings can be downloaded from the below link:

Additional file(s)
  • Cloutier2012 - Feedback motif for Parkinson's disease:
    Copasi file of the model
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