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BIOMD0000000285 - Tang2010_PolyGlutamate

 

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Reference Publication
Publication ID: 20885783
Tang MY, Proctor CJ, Woulfe J, Gray DA.
Experimental and computational analysis of polyglutamine-mediated cytotoxicity.
PLoS Comput. Biol. 2010; 6(9): 134-136
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.  [more]
Model
Original Model: Proctor_PolyQ
Submitter: Carole Proctor
Submission ID: MODEL1002250000
Submission Date: 25 Feb 2010 15:44:53 UTC
Last Modification Date: 03 Jun 2014 21:03:59 UTC
Creation Date: 27 Sep 2010 12:21:56 UTC
Encoders:  Vijayalakshmi Chelliah
   Carole J Proctor
set #1
bqbiol:hasVersion Human Disease Ontology DOID:1289
set #2
bqmodel:isDerivedFrom BioModels Database Proctor2007_ubiquitine
set #3
bqbiol:hasTaxon Taxonomy Mammalia
set #4
bqbiol:isVersionOf Gene Ontology pathogenesis
Gene Ontology protein polyglutamylation
Notes

This a model from the article:
Experimental and computational analysis of polyglutamine-mediated cytotoxicity.
Tang MY, Proctor CJ, Woulfe J, Gray DA. PLoS Comput Biol.2010 Sep 23;6(9). 20885783,
Abstract:
Expanded polyglutamine (polyQ) proteins are known to be the causative agents of a number of human neurodegenerative diseases but the molecular basis of their cytoxicity is still poorly understood. PolyQ tracts may impede the activity of the proteasome, and evidence from single cell imaging suggests that the sequestration of polyQ into inclusion bodies can reduce the proteasomal burden and promote cell survival, at least in the short term. The presence of misfolded protein also leads to activation of stress kinases such as p38MAPK, which can be cytotoxic. The relationships of these systems are not well understood. We have used fluorescent reporter systems imaged in living cells, and stochastic computer modeling to explore the relationships of polyQ, p38MAPK activation, generation of reactive oxygen species (ROS), proteasome inhibition, and inclusion body formation. In cells expressing a polyQ protein inclusion, body formation was preceded by proteasome inhibition but cytotoxicity was greatly reduced by administration of a p38MAPK inhibitor. Computer simulations suggested that without the generation of ROS, the proteasome inhibition and activation of p38MAPK would have significantly reduced toxicity. Our data suggest a vicious cycle of stress kinase activation and proteasome inhibition that is ultimately lethal to cells. There was close agreement between experimental data and the predictions of a stochastic computer model, supporting a central role for proteasome inhibition and p38MAPK activation in inclusion body formation and ROS-mediated cell death.

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team.
For more information see the terms of use.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Model
Publication ID: 20885783 Submission Date: 25 Feb 2010 15:44:53 UTC Last Modification Date: 03 Jun 2014 21:03:59 UTC Creation Date: 27 Sep 2010 12:21:56 UTC
Mathematical expressions
Reactions
polyQSynthesis polyqProteasomeBinding polyqProteasomeRelease PolyQDegradation
mRFPuSynthesis mRFPuProteasomeBinding mRFPuProteasomeRelease mRFPuDegradation
PolyQAggregation1 PolyQAggregation2 PolyQAggregation3 PolyQAggregation4
PolyQAggregation5 PolyQDisaggregation5 PolyQDisaggregation4 PolyQDisaggregation3
PolyQDisaggregation2 PolyQDisaggregation1 PolyQInclusionFormation PolyQInclusionGrowth
ProteasomeInhibition1 ProteasomeInhibition2 ProteasomeInhibition3 ProteasomeInhibition4
ProteasomeInhibition5 mRFPuProteasomeSequestering mRFPuSequestering ROSgenerationBasal
ROSgenerationSmallAggPolyQ1 ROSgenerationSmallAggPolyQ2 ROSgenerationSmallAggPolyQ3 ROSgenerationSmallAggPolyQ4
ROSgenerationSmallAggPolyQ5 ROSgenerationAggPProteasome ROSremoval p38activation
p38inactivation AggP_ProteasomeSequestering PolyQ_ProteasomeSequestering MisP_ProteasomeSequestering
ProteinSynthesis Misfolding Refolding MisP_ProteasomeBinding
MisP_ProteasomeRelease MisP_Degradation MisP_Aggregation1 MisP_Aggregation2
MisP_Aggregation3 MisP_Aggregation4 MisP_Aggregation5 MisP_Disaggregation1
MisP_Disaggregation2 MisP_Disaggregation3 MisP_Disaggregation4 MisP_Disaggregation5
MisP_InclusionFormation MisPInclusionGrowth ProteasomeInhibitionAggP1 ProteasomeInhibitionAggP2
ProteasomeInhibitionAggP3 ProteasomeInhibitionAggP4 ProteasomeInhibitionAggP5 ROSgenerationSmallAggP1
ROSgenerationSmallAggP2 ROSgenerationSmallAggP3 ROSgenerationSmallAggP4 ROSgenerationSmallAggP5
p38_P_ROS_Generation ROSgenerationSeqAggP P38DeathPathway PIDeathPathway
Rules
Assignment Rule (variable: oligomers)      
Events
PIcellDeath p38cellDeath    
Physical entities
Compartments Species
cytosol PolyQ Proteasome NatP
MisP MisP_Proteasome AggP1
AggP2 AggP3 AggP4
AggP5 AggPolyQ1 AggPolyQ2
AggPolyQ3 AggPolyQ4 AggPolyQ5
SeqAggP AggP_Proteasome mRFPu
mRFPu_Proteasome PolyQ_Proteasome ROS
p38_P p38 Source
Sink p38death PIdeath
Global parameters
kaggPolyQ kdisaggPolyQ1 kdisaggPolyQ2 kdisaggPolyQ3
kdisaggPolyQ4 kdisaggPolyQ5 kseqPolyQ kinhprot
kaggMisP kagg2MisP kdisaggMisP1 kdisaggMisP2
kdisaggMisP3 kdisaggMisP4 kdisaggMisP5 ksynmRFPu
kbinmRFPu krelmRFPu kdegmRFPu ksynPolyQ
kbinPolyQ krelPolyQ kdegPolyQ kgenROS
kremROS kgenROSAggP kgenROSSeqAggP kactp38
kinactp38 kseqMisP kseqAggPProt kseqPolyQProt
kseqMisPProt kseqmRFPuProt kseqmRFPu ksynNatP
kmisfold krefold kbinMisPProt krelMisPProt
kdegMisP kgenROSp38 kp38act kp38death
kPIdeath kproteff kalive oligomers
Reactions (72)
 
 polyQSynthesis [Source] → [PolyQ];  
 
 polyqProteasomeBinding [PolyQ] + [Proteasome] → [PolyQ_Proteasome];  
 
 polyqProteasomeRelease [PolyQ_Proteasome] → [PolyQ] + [Proteasome];  
 
 PolyQDegradation [PolyQ_Proteasome] → [Proteasome];  
 
 mRFPuSynthesis [Source] → [mRFPu];  
 
 mRFPuProteasomeBinding [mRFPu] + [Proteasome] → [mRFPu_Proteasome];  
 
 mRFPuProteasomeRelease [mRFPu_Proteasome] → [mRFPu] + [Proteasome];  
 
 mRFPuDegradation [mRFPu_Proteasome] → [Proteasome];  
 
 PolyQAggregation1 2.0 × [PolyQ] + [ROS] → [AggPolyQ1] + [ROS];  
 
 PolyQAggregation2 [PolyQ] + [AggPolyQ1] + [ROS] → [AggPolyQ2] + [ROS];  
 
 PolyQAggregation3 [PolyQ] + [AggPolyQ2] + [ROS] → [AggPolyQ3] + [ROS];  
 
 PolyQAggregation4 [PolyQ] + [AggPolyQ3] + [ROS] → [AggPolyQ4] + [ROS];  
 
 PolyQAggregation5 [PolyQ] + [AggPolyQ4] + [ROS] → [AggPolyQ5] + [ROS];  
 
 PolyQDisaggregation5 [AggPolyQ5] → [PolyQ] + [AggPolyQ4];  
 
 PolyQDisaggregation4 [AggPolyQ4] → [PolyQ] + [AggPolyQ3];  
 
 PolyQDisaggregation3 [AggPolyQ3] → [PolyQ] + [AggPolyQ2];  
 
 PolyQDisaggregation2 [AggPolyQ2] → [PolyQ] + [AggPolyQ1];  
 
 PolyQDisaggregation1 [AggPolyQ1] → 2.0 × [PolyQ];  
 
 PolyQInclusionFormation [PolyQ] + [AggPolyQ5] → 7.0 × [SeqAggP];  
 
 PolyQInclusionGrowth [PolyQ] + [SeqAggP] → 2.0 × [SeqAggP];  
 
 ProteasomeInhibition1 [AggPolyQ1] + [Proteasome] → [AggP_Proteasome];  
 
 ProteasomeInhibition2 [AggPolyQ2] + [Proteasome] → [AggP_Proteasome];  
 
 ProteasomeInhibition3 [AggPolyQ3] + [Proteasome] → [AggP_Proteasome];  
 
 ProteasomeInhibition4 [AggPolyQ4] + [Proteasome] → [AggP_Proteasome];  
 
 ProteasomeInhibition5 [AggPolyQ5] + [Proteasome] → [AggP_Proteasome];  
 
 mRFPuProteasomeSequestering [mRFPu_Proteasome] + [SeqAggP] → 2.0 × [SeqAggP];  
 
 mRFPuSequestering [mRFPu] + [SeqAggP] → 2.0 × [SeqAggP];  
 
 ROSgenerationBasal [Source] → [ROS];  
 
 ROSgenerationSmallAggPolyQ1 [AggPolyQ1] → [AggPolyQ1] + [ROS];  
 
 ROSgenerationSmallAggPolyQ2 [AggPolyQ2] → [AggPolyQ2] + [ROS];  
 
 ROSgenerationSmallAggPolyQ3 [AggPolyQ3] → [AggPolyQ3] + [ROS];  
 
 ROSgenerationSmallAggPolyQ4 [AggPolyQ4] → [AggPolyQ4] + [ROS];  
 
 ROSgenerationSmallAggPolyQ5 [AggPolyQ5] → [AggPolyQ5] + [ROS];  
 
 ROSgenerationAggPProteasome [AggP_Proteasome] → [AggP_Proteasome] + [ROS];  
 
 ROSremoval [ROS] → [Sink];  
 
 p38activation [ROS] + [p38] → [ROS] + [p38_P];  
 
 p38inactivation [p38_P] → [p38];  
 
 AggP_ProteasomeSequestering [AggP_Proteasome] + [SeqAggP] → 2.0 × [SeqAggP];  
 
 PolyQ_ProteasomeSequestering [PolyQ_Proteasome] + [SeqAggP] → 2.0 × [SeqAggP];  
 
 MisP_ProteasomeSequestering [MisP_Proteasome] + [SeqAggP] → 2.0 × [SeqAggP];  
 
 ProteinSynthesis [Source] → [NatP];  
 
 Misfolding [NatP] + [ROS] → [MisP] + [ROS];  
 
 Refolding [MisP] → [NatP];  
 
 MisP_ProteasomeBinding [MisP] + [Proteasome] → [MisP_Proteasome];  
 
 MisP_ProteasomeRelease [MisP_Proteasome] → [MisP] + [Proteasome];  
 
 MisP_Degradation [MisP_Proteasome] → [Proteasome];  
 
 MisP_Aggregation1 2.0 × [MisP] → [AggP1];  
 
 MisP_Aggregation2 [MisP] + [AggP1] → [AggP2];  
 
 MisP_Aggregation3 [MisP] + [AggP2] → [AggP3];  
 
 MisP_Aggregation4 [MisP] + [AggP3] → [AggP4];  
 
 MisP_Aggregation5 [MisP] + [AggP4] → [AggP5];  
 
 MisP_Disaggregation1 [AggP1] → 2.0 × [MisP];  
 
 MisP_Disaggregation2 [AggP2] → [MisP] + [AggP1];  
 
 MisP_Disaggregation3 [AggP3] → [MisP] + [AggP2];  
 
 MisP_Disaggregation4 [AggP4] → [MisP] + [AggP3];  
 
 MisP_Disaggregation5 [AggP5] → [MisP] + [AggP4];  
 
 MisP_InclusionFormation [MisP] + [AggP5] → 7.0 × [SeqAggP];  
 
 MisPInclusionGrowth [MisP] + [SeqAggP] → 2.0 × [SeqAggP];  
 
 ProteasomeInhibitionAggP1 [AggP1] + [Proteasome] → [AggP_Proteasome];  
 
 ProteasomeInhibitionAggP2 [AggP2] + [Proteasome] → [AggP_Proteasome];  
 
 ProteasomeInhibitionAggP3 [AggP3] + [Proteasome] → [AggP_Proteasome];  
 
 ProteasomeInhibitionAggP4 [AggP4] + [Proteasome] → [AggP_Proteasome];  
 
 ProteasomeInhibitionAggP5 [AggP5] + [Proteasome] → [AggP_Proteasome];  
 
 ROSgenerationSmallAggP1 [AggP1] → [AggP1] + [ROS];  
 
 ROSgenerationSmallAggP2 [AggP2] → [AggP2] + [ROS];  
 
 ROSgenerationSmallAggP3 [AggP3] → [AggP3] + [ROS];  
 
 ROSgenerationSmallAggP4 [AggP4] → [AggP4] + [ROS];  
 
 ROSgenerationSmallAggP5 [AggP5] → [AggP5] + [ROS];  
 
 p38_P_ROS_Generation [p38_P] → [p38_P] + [ROS];  
 
 ROSgenerationSeqAggP [SeqAggP] → [SeqAggP] + [ROS];  
 
 P38DeathPathway [p38_P] → [p38_P] + [p38death];  
 
 PIDeathPathway [AggP_Proteasome] → [AggP_Proteasome] + [PIdeath];  
 
Rules (1)
 
 Assignment Rule (name: oligomers) oligomers = AggPolyQ1+AggPolyQ2+AggPolyQ3+AggPolyQ4+AggPolyQ5
 
Events (2)
 
 PIcellDeath
kalive = 0
 
 p38cellDeath
kalive = 0
 
   Spatial dimensions: 3.0  Compartment size: 1.0
 
 PolyQ
Compartment: cytosol
Initial amount: 1000.0
 
 Proteasome
Compartment: cytosol
Initial amount: 1000.0
 
   NatP
Compartment: cytosol
Initial amount: 19500.0
 
   MisP
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Proteasome
Compartment: cytosol
Initial amount: 0.0
 
   AggP1
Compartment: cytosol
Initial amount: 0.0
 
   AggP2
Compartment: cytosol
Initial amount: 0.0
 
   AggP3
Compartment: cytosol
Initial amount: 0.0
 
   AggP4
Compartment: cytosol
Initial amount: 0.0
 
   AggP5
Compartment: cytosol
Initial amount: 0.0
 
   AggPolyQ1
Compartment: cytosol
Initial amount: 0.0
 
   AggPolyQ2
Compartment: cytosol
Initial amount: 0.0
 
   AggPolyQ3
Compartment: cytosol
Initial amount: 0.0
 
   AggPolyQ4
Compartment: cytosol
Initial amount: 0.0
 
   AggPolyQ5
Compartment: cytosol
Initial amount: 0.0
 
   SeqAggP
Compartment: cytosol
Initial amount: 0.0
 
   AggP_Proteasome
Compartment: cytosol
Initial amount: 0.0
 
   mRFPu
Compartment: cytosol
Initial amount: 300.0
 
   mRFPu_Proteasome
Compartment: cytosol
Initial amount: 0.0
 
   PolyQ_Proteasome
Compartment: cytosol
Initial amount: 0.0
 
   ROS
Compartment: cytosol
Initial amount: 10.0
 
   p38_P
Compartment: cytosol
Initial amount: 0.0
 
   p38
Compartment: cytosol
Initial amount: 100.0
 
   Source
Compartment: cytosol
Initial amount: 1.0
Constant
 
   Sink
Compartment: cytosol
Initial amount: 1.0
Constant
 
   p38death
Compartment: cytosol
Initial amount: 0.0
 
   PIdeath
Compartment: cytosol
Initial amount: 0.0
 
Global Parameters (48)
 
   kaggPolyQ
Value: 5.0E-8
Constant
 
   kdisaggPolyQ1
Value: 5.0E-7
Constant
 
   kdisaggPolyQ2
Value: 4.0E-7
Constant
 
   kdisaggPolyQ3
Value: 3.0E-7
Constant
 
   kdisaggPolyQ4
Value: 2.0E-7
Constant
 
   kdisaggPolyQ5
Value: 1.0E-7
Constant
 
   kseqPolyQ
Value: 8.0E-7
Constant
 
   kinhprot
Value: 5.0E-9
Constant
 
   kaggMisP
Value: 1.0E-11
Constant
 
   kagg2MisP
Value: 1.0E-10
Constant
 
   kdisaggMisP1
Value: 5.0E-7
Constant
 
   kdisaggMisP2
Value: 4.0E-7
Constant
 
   kdisaggMisP3
Value: 3.0E-7
Constant
 
   kdisaggMisP4
Value: 2.0E-7
Constant
 
   kdisaggMisP5
Value: 1.0E-7
Constant
 
   ksynmRFPu
Value: 0.138
Constant
 
   kbinmRFPu
Value: 5.0E-7
Constant
 
   krelmRFPu
Value: 1.0E-8
Constant
 
   kdegmRFPu
Value: 0.0050
Constant
 
   ksynPolyQ
Value: 0.0070
Constant
 
   kbinPolyQ
Value: 5.0E-8
Constant
 
   krelPolyQ
Value: 1.0E-9
Constant
 
   kdegPolyQ
Value: 0.0025
Constant
 
   kgenROS
Value: 0.0017
Constant
 
   kremROS
Value: 2.0E-4
Constant
 
   kgenROSAggP
Value: 5.0E-6
Constant
 
   kgenROSSeqAggP
Value: 1.0E-7
Constant
 
   kactp38
Value: 5.0E-6
Constant
 
   kinactp38
Value: 0.0020
Constant
 
   kseqMisP
Value: 1.0E-9
Constant
 
   kseqAggPProt
Value: 5.0E-7
Constant
 
   kseqPolyQProt
Value: 5.0E-7
Constant
 
   kseqMisPProt
Value: 5.0E-7
Constant
 
   kseqmRFPuProt
Value: 5.0E-7
Constant
 
   kseqmRFPu
Value: 1.0E-10
Constant
 
   ksynNatP
Value: 2.4
Constant
 
   kmisfold
Value: 2.0E-6
Constant
 
   krefold
Value: 8.0E-5
Constant
 
   kbinMisPProt
Value: 5.0E-8
Constant
 
   krelMisPProt
Value: 1.0E-8
Constant
 
   kdegMisP
Value: 0.01
Constant
 
   kgenROSp38
Value: 7.0E-4
Constant
 
   kp38act
Value: 1.0
 
   kp38death
Value: 9.0E-8
Constant
 
   kPIdeath
Value: 2.5E-8
Constant
 
   kproteff
Value: 1.0
 
   kalive
Value: 1.0
 
   oligomers
Value: NaN
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000285

Curator's comment: (updated: 07 Dec 2010 16:29:07 GMT)

The model reproduces figure S2 of the Supplementary material of the reference publication. In the paper, figure S2 is generated by picking 3 stochastic simulation runs and plotted the monomer, oligomers and inclusion bodies. There is slight inconsistency between the plots obtained here (curation figure) and that of the paper (figure S2). The curation figure is obtained using deterministic simulation run, whereas in the paper figure S2 is obtained using stochastic simulation run. The inconsistency is due to the difference in the stochastic and deterministic simulation runs. This has been checked with the author.
The model was integrated and simulated using Copasi v4.6 (Build 32).

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