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Related Publication
  • Experimental and computational analysis of polyglutamine-mediated cytotoxicity.
  • Tang MY, Proctor CJ, Woulfe J, Gray DA
  • PLoS computational biology , 9/ 2010 , Volume 6
  • Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • 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.
Carole Proctor

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BIOMD0000000285.xml.origin SBML L2V3 representation of Tang2010_PolyGlutamate 56.40 KB Preview | Download

  • Model originally submitted by : Carole Proctor
  • Submitted: Feb 25, 2010 3:44:53 PM
  • Last Modified: Jun 3, 2014 10:03:59 PM
  • Version: 2 public model Download this version
    • Submitted on: Jun 3, 2014 10:03:59 PM
    • Submitted by: Carole Proctor
    • With comment: Current version of Tang2010_PolyGlutamate
  • Version: 1 public model Download this version
    • Submitted on: Feb 25, 2010 3:44:53 PM
    • Submitted by: Carole Proctor
    • With comment: Original import of BIOMD0000000285.xml.origin
Curator's comment:
(added: 07 Dec 2010, 16:29:07, updated: 07 Dec 2010, 16:29:07)
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).