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Proctor2010 - a link between GSK3 and p53 in Alzheimer's Disease

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SBML (L2V3)
Related Publication
  • GSK3 and p53 - is there a link in Alzheimer's disease?
  • Proctor CJ, Gray DA
  • Molecular neurodegeneration , 0/ 2010 , Volume 5 , pages: 7
  • Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK. c.j.proctor@ncl.ac.uk.
  • BACKGROUND: Recent evidence suggests that glycogen synthase kinase-3beta (GSK3beta) is implicated in both sporadic and familial forms of Alzheimer's disease. The transcription factor, p53 also plays a role and has been linked to an increase in tau hyperphosphorylation although the effect is indirect. There is also evidence that GSK3beta and p53 interact and that the activity of both proteins is increased as a result of this interaction. Under normal cellular conditions, p53 is kept at low levels by Mdm2 but when cells are stressed, p53 is stabilised and may then interact with GSK3beta. We propose that this interaction has an important contribution to cellular outcomes and to test this hypothesis we developed a stochastic simulation model. RESULTS: The model predicts that high levels of DNA damage leads to increased activity of p53 and GSK3beta and low levels of aggregation but if DNA damage is repaired, the aggregates are eventually cleared. The model also shows that over long periods of time, aggregates may start to form due to stochastic events leading to increased levels of ROS and damaged DNA. This is followed by increased activity of p53 and GSK3beta and a vicious cycle ensues. CONCLUSIONS: Since p53 and GSK3beta are both involved in the apoptotic pathway, and GSK3beta overactivity leads to increased levels of plaques and tangles, our model might explain the link between protein aggregation and neuronal loss in neurodegeneration.
Contributors
Carole Proctor

Metadata information

Curation status
Curated
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Model files

BIOMD0000000286.xml.origin SBML L2V3 representation of Proctor2010 - a link between GSK3 and p53 in Alzheimer\s Disease 71.32 KB Preview | Download

  • Model originally submitted by : Carole Proctor
  • Submitted: Nov 3, 2009 4:35:40 PM
  • Last Modified: Oct 10, 2014 12:16:03 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Oct 10, 2014 12:16:03 PM
    • Submitted by: Carole Proctor
    • With comment: Current version of Proctor2010 - a link between GSK3 and p53 in Alzheimer's Disease
  • Version: 1 public model Download this version
    • Submitted on: Nov 3, 2009 4:35:40 PM
    • Submitted by: Carole Proctor
    • With comment: Original import of BIOMD0000000286.xml.origin
Curator's comment:
(added: 13 Dec 2010, 11:39:31, updated: 13 Dec 2010, 11:39:31)
The model was integrated using Copasi v4.6 (Build 32). The Stochastic simulation run using Stochastic (Gribson & Bruck) method. The model reproduces figures corresponding to figure 4 of the paper.