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  • Modelling the role of the Hsp70/Hsp90 system in the maintenance of protein homeostasis.
  • Proctor CJ, Lorimer IA
  • PloS one , 0/ 2011 , Volume 6 , pages: e22038
  • Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • Neurodegeneration is an age-related disorder which is characterised by the accumulation of aggregated protein and neuronal cell death. There are many different neurodegenerative diseases which are classified according to the specific proteins involved and the regions of the brain which are affected. Despite individual differences, there are common mechanisms at the sub-cellular level leading to loss of protein homeostasis. The two central systems in protein homeostasis are the chaperone system, which promotes correct protein folding, and the cellular proteolytic system, which degrades misfolded or damaged proteins. Since these systems and their interactions are very complex, we use mathematical modelling to aid understanding of the processes involved. The model developed in this study focuses on the role of Hsp70 (IPR00103) and Hsp90 (IPR001404) chaperones in preventing both protein aggregation and cell death. Simulations were performed under three different conditions: no stress; transient stress due to an increase in reactive oxygen species; and high stress due to sustained increases in reactive oxygen species. The model predicts that protein homeostasis can be maintained during short periods of stress. However, under long periods of stress, the chaperone system becomes overwhelmed and the probability of cell death pathways being activated increases. Simulations were also run in which cell death mediated by the JNK (P45983) and p38 (Q16539) pathways was inhibited. The model predicts that inhibiting either or both of these pathways may delay cell death but does not stop the aggregation process and that eventually cells die due to aggregated protein inhibiting proteasomal function. This problem can be overcome if the sequestration of aggregated protein into inclusion bodies is enhanced. This model predicts responses to reactive oxygen species-mediated stress that are consistent with currently available experimental data. The model can be used to assess specific interventions to reduce cell death due to impaired protein homeostasis.
Carole Proctor, administrator

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Model files

BIOMD0000000344.xml.origin SBML L2V3 representation of Proctor2011_ProteinHomeostasis_NormalCondition 64.55 KB Preview | Download

Additional files

MODEL1005280000_moderatestress.xml To obtain this plot, ROS levels should be increased by a factor of 4 at time = 4 hours for a period of 1 hour. 68.46 KB Preview | Download
MODEL1005280000_highstress.xml To obtain this plot, constant rate of ROS production should be replaced with a rate that increases linearly with time. This is done by including a time variable in the rate law. 68.06 KB Preview | Download

  • Model originally submitted by : Carole Proctor
  • Submitted: May 28, 2010 11:45:33 AM
  • Last Modified: Dec 21, 2018 5:14:07 PM
  • Version: 3 public model Download this version
    • Submitted on: Dec 21, 2018 5:14:07 PM
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: MODEL1005280000_moderatestress.xml, MODEL1005280000_highstress.xml
  • Version: 2 public model Download this version
    • Submitted on: Apr 8, 2016 6:01:52 PM
    • Submitted by: Carole Proctor
    • With comment: Current version of Proctor2011_ProteinHomeostasis_NormalCondition
  • Version: 1 public model Download this version
    • Submitted on: May 28, 2010 11:45:33 AM
    • Submitted by: Carole Proctor
    • With comment: Original import of BIOMD0000000344.xml.origin
Curator's comment:
(added: 21 Jul 2011, 17:38:42, updated: 21 Jul 2011, 17:38:42)
Simulations were performed under three different conditions: 1) normal condition (no stress), 2) moderate stress due to an increase in reactive oxygen species (ROS) i.e. ROS levels were increased by a factor of 4 at time=4hours for a period of 1 hour (not 2 hours as mentioned in the figure 5 legend of the reference publication. This is, a typo in the paper and is clarified by the author) [Refer supporting file: MODEL1005280000_moderatestress.xml] and 3) high stress due to sustained increase in reactive oxygen species (ROS) (here ROS increases with time) [Refer supporting file:MODEL1005280000_highstress.xml]. Supplementary figures S3 (normal condition), S4 (moderate stress condition) and S6 (high stress condition) are reproduced here. SBML odeSolver was used for model simulation and plots were generated using gnuplot.