Dataset Information

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

ABSTRACT: This is the model described the article: GSK3 and p53 - is there a link in Alzheimer's disease? Carole J Proctor and Douglas A Gray Molecular Neurodegeneration 2010, 5:7; doi: 10.1186/1750-1326-5-7 Abstract: 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. Notes: The original model submitted by the author had events in it. Since, this model is intended for Stochastic Simulation run and Copasi cannot handle events in Stochastic run, I have replaced the events with piecewise assignment rule. -Viji This model is an extension of Proctor_p53_Mdm2_ATM ( BIOMD0000000188 ). 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.

DISEASE(S): Alzheimer's Disease

SUBMITTER: Carole Proctor

PROVIDER: BIOMD0000000286 | BioModels | 2010-01-27

REPOSITORIES: BioModels

ACCESS DATA

Publications

GSK3 and p53 - is there a link in Alzheimer's disease?

Proctor Carole J CJ Gray Douglas A DA

Molecular neurodegeneration 20100126

<h4>Background</h4>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 ...[more]

PMID: 20181016

Similar Datasets

Project description:Proctor2012 - Amyloid-beta aggregation This model supports the current thinking that levels of dimers are important in initiating the aggregation process. This model is described in the article: Aggregation, impaired degradation and immunization targeting of amyloid-beta dimers in Alzheimer's disease: a stochastic modelling approach. Proctor CJ, Pienaar IS, Elson JL, Kirkwood TB Molecular Neurodegeneration. 2012; 7:32 Abstract: BACKGROUND: Alzheimer's disease (AD) is the most frequently diagnosed neurodegenerative disorder affecting humans, with advanced age being the most prominent risk factor for developing AD. Despite intense research efforts aimed at elucidating the precise molecular underpinnings of AD, a definitive answer is still lacking. In recent years, consensus has grown that dimerisation of the polypeptide amyloid-beta (Aß), particularly Aß₄₂, plays a crucial role in the neuropathology that characterise AD-affected post-mortem brains, including the large-scale accumulation of fibrils, also referred to as senile plaques. This has led to the realistic hope that targeting Aß₄₂ immunotherapeutically could drastically reduce plaque burden in the ageing brain, thus delaying AD onset or symptom progression. Stochastic modelling is a useful tool for increasing understanding of the processes underlying complex systems-affecting disorders such as AD, providing a rapid and inexpensive strategy for testing putative new therapies. In light of the tool's utility, we developed computer simulation models to examine Aß₄₂ turnover and its aggregation in detail and to test the effect of immunization against Aß dimers. RESULTS: Our model demonstrates for the first time that even a slight decrease in the clearance rate of Aß₄₂ monomers is sufficient to increase the chance of dimers forming, which could act as instigators of protofibril and fibril formation, resulting in increased plaque levels. As the process is slow and levels of Aβ are normally low, stochastic effects are important. Our model predicts that reducing the rate of dimerisation leads to a significant reduction in plaque levels and delays onset of plaque formation. The model was used to test the effect of an antibody mediated immunological response. Our results showed that plaque levels were reduced compared to conditions where antibodies are not present. CONCLUSION: Our model supports the current thinking that levels of dimers are important in initiating the aggregation process. Although substantial knowledge exists regarding the process, no therapeutic intervention is on offer that reliably decreases disease burden in AD patients. Computer modelling could serve as one of a number of tools to examine both the validity of reliable biomarkers and aid the discovery of successful intervention strategies. This model is hosted on BioModels Database and identified by: BIOMD0000000462 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

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

Publications

GSK3 and p53 - is there a link in Alzheimer's disease?

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure