Design principles of ROS dynamic networks relevant to precision therapies for age-related diseases

The eminently complex regulatory network protecting the cell against oxidative stress, surfaces in several disease maps, including that of Parkinson9s disease (PD). How this molecular networking achieves its various functionalities and how processes operating at the seconds-minutes time scale cause a disease at a time scale of multiple decennia is enigmatic. By computational analysis, we here disentangle the reactive oxygen species (ROS) regulatory network into a hierarchy of subnetworks that each correspond to a different functionality. The detailed dynamic model of ROS management obtained integrates these functionalities and fits in vitro data sets from two different laboratories. The model shows effective ROS-management for a century, followed by a sudden system9s collapse due to the loss of p62 protein. PD related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the system9s collapse. Various in-silico interventions (e.g. addition of antioxidants or caffeine) slowed down the collapse of the system in silico, suggesting the model may help discover new medicinal and nutritional therapies.