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ROS networks: designs, aging, Parkinson’s disease and precision therapies
npj Systems Biology and Applications ( IF 3.5 ) Pub Date : 2020-10-26 , DOI: 10.1038/s41540-020-00150-w
Alexey N Kolodkin 1, 2, 3, 4 , Raju Prasad Sharma 3, 5 , Anna Maria Colangelo 6, 7, 8 , Andrew Ignatenko 9 , Francesca Martorana 6, 7, 8 , Danyel Jennen 10 , Jacco J Briedé 10 , Nathan Brady 11 , Matteo Barberis 4, 12, 13 , Thierry D G A Mondeel 4, 12, 13 , Michele Papa 7, 14, 15 , Vikas Kumar 5, 16 , Bernhard Peters 17 , Alexander Skupin 2 , Lilia Alberghina 6, 7 , Rudi Balling 2 , Hans V Westerhoff 1, 3, 4, 18
Affiliation  

How the network around ROS protects against oxidative stress and Parkinson’s disease (PD), and how processes at the minutes timescale cause disease and aging after decades, remains enigmatic. Challenging whether the ROS network is as complex as it seems, we built a fairly comprehensive version thereof which we disentangled into a hierarchy of only five simpler subnetworks each delivering one type of robustness. The comprehensive dynamic model described in vitro data sets from two independent laboratories. Notwithstanding its five-fold robustness, it exhibited a relatively sudden breakdown, after some 80 years of virtually steady performance: it predicted aging. PD-related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the collapse, while antioxidants or caffeine retarded it. Introducing a new concept (aging-time-control coefficient), we found that as many as 25 out of 57 molecular processes controlled aging. We identified new targets for “life-extending interventions”: mitochondrial synthesis, KEAP1 degradation, and p62 metabolism.



中文翻译:


ROS 网络:设计、衰老、帕金森病和精准治疗



ROS 周围的网络如何防止氧化应激和帕金森病 (PD),以及几分钟内的过程如何在几十年后导致疾病和衰老,仍然是个谜。为了质疑 ROS 网络是否像看起来那么复杂,我们构建了一个相当全面的版本,我们将其分解为仅由五个更简单的子网络组成的层次结构,每个子网络提供一种类型的稳健性。综合动态模型描述了来自两个独立实验室的体外数据集。尽管其稳健性提高了五倍,但在大约 80 年几乎稳定的性能之后,它表现出了相对突然的崩溃:它预测了衰老。与 PD 相关的情况,例如缺乏 DJ-1 蛋白或增加 α-突触核蛋白,加速了崩溃,而抗氧化剂或咖啡因则延缓了崩溃。引入新概念(老化时间控制系数),我们发现 57 个分子过程中有多达 25 个控制老化。我们确定了“延长生命干预措施”的新目标:线粒体合成、KEAP1 降解和 p62 代谢。

更新日期:2020-10-28
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