Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
Mol Neurodegener. 2010 Jan 26;5:7. doi: 10.1186/1750-1326-5-7.
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.
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.
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.
最近的证据表明，糖原合成酶激酶-3β（GSK3β）与散发性和家族性阿尔茨海默病都有关。转录因子 p53 也发挥作用，并与 tau 过度磷酸化的增加有关，尽管这种影响是间接的。还有证据表明 GSK3β 和 p53 相互作用，并且由于这种相互作用，两种蛋白质的活性都增加。在正常的细胞条件下，p53 被 Mdm2 保持在低水平，但当细胞受到压力时，p53 被稳定下来，然后可能与 GSK3β 相互作用。我们提出这种相互作用对细胞结果有重要贡献，并为了验证这一假设，我们开发了一个随机模拟模型。
该模型预测高水平的 DNA 损伤会导致 p53 和 GSK3β 的活性增加，以及低水平的聚集，但如果 DNA 损伤得到修复，聚集物最终会被清除。该模型还表明，在很长一段时间内，由于随机事件，聚集物可能开始形成，从而导致 ROS 和受损 DNA 水平升高。随后是 p53 和 GSK3β 的活性增加，并形成恶性循环。
由于 p53 和 GSK3β 都参与了细胞凋亡途径，并且 GSK3β 的过度活跃会导致斑块和缠结的水平增加，我们的模型可能解释了蛋白聚集和神经退行性变中神经元丧失之间的联系。
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