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BIOMD0000000285
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is described by: http://identifiers.org/pubmed/20885783
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name: Tang2010_PolyGlutamate
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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 …
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003222
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002335
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002299
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type: SpeciesReference

511769
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type: Parameter

511568
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initial concentration: NaN
initial amount: 0.0
in compartment: 511542
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003463
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004939
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003402
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003318
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002520
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002933
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002007
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511544
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constant: false
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has only substance units: true
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in compartment: 511542
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003390
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type: SpeciesReference

004235
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species: 511551
type: SpeciesReference

511567
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in compartment: 511542
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005000
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species: 511561
type: SpeciesReference

001874
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species: 511563
type: SpeciesReference

004575
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species: 511562
type: SpeciesReference

511545
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constant: false
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has only substance units: true
initial concentration: NaN
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in compartment: 511542
type: Species

002287
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002482
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species: 511556
type: SpeciesReference

001813
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005109
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511555
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003234
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species: 511567
type: SpeciesReference

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001923
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511625
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511611
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003114
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type: SpeciesReference

511595
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type: Reaction

002665
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species: 511561
type: SpeciesReference

004175
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511639
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511585
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type: Reaction

511564
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in compartment: 511542
type: Species

511553
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003644
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511593
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type: Reaction

511626
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type: Reaction

511612
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product: 003234
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type: Reaction

002763
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species: 511562
type: SpeciesReference

002714
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species: 511562
type: SpeciesReference

511594
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type: Reaction

003306
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species: 511562
type: SpeciesReference

511584
kinetic law: 001959
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type: Reaction

001838
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species: 511570
type: SpeciesReference

511613
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type: Reaction

511550
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in compartment: 511542
type: Species

001935
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species: 511563
type: SpeciesReference

004599
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species: 511553
type: SpeciesReference

511623
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type: Reaction

511563
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in compartment: 511542
type: Species

003126
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species: 511556
type: SpeciesReference

002177
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species: 511558
type: SpeciesReference

511577
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type: Reaction

004721
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species: 511567
type: SpeciesReference

004187
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species: 511550
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511597
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type: Reaction

002031
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species: 511555
type: SpeciesReference

511583
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product: 001899
reactant: 001887
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type: Reaction

005158
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type: Trigger

003704
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species: 511567
type: SpeciesReference

511581
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type: Reaction

511551
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004271
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511562
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003993
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511624
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002751
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511596
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002616
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002702
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type: SpeciesReference

004090
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002408
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species: 511559
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511629
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type: Reaction

001947
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511561
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002043
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511615
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002690
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511635
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type: Reaction

511560
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002165
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511589
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511599
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511570
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002640
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002604
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511616
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002092
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002556
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002787
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004417
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511588
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511636
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type: Reaction

003909
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003981
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002653
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511573
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005048
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511627
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005134
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003330
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511617
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511587
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511637
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type: Reaction

002360
stoichiometry: 1.0
species: 511560
type: SpeciesReference

W3 CDTF: Mon Sep 27 13:21:56 BST 2010

004102
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species: 511554
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511647
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002153
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002080
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511572
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511628
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002568
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511618
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511638
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003632
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511586
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002799
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511571
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511648
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004163
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species: 511551
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004405
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species: 511547
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W3 CDTF: Wed Dec 22 10:49:21 GMT 2010