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

Alexey Kolodkin, Raju Prasad Sharma, Anna Maria Colangelo, Andrew Ignatenko, Francesca Martorana, Danyel Jennen, Jacco J. Briede, Nathan Brady, Matteo Barberis, Thierry D.G.A. Mondeel, Michele Papa, Vikas Kumar, Bernhard Peters, Alexander Skupin, Lilia Alberghina, Rudi Balling, Hans V. Westerhoff

Research output: Contribution to journalArticlepeer-review

Abstract

The eminently complex regulatory network protecting the cell against oxidative stress, surfaces in several disease maps, including that of Parkinson’s 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 system’s collapse due to the loss of p62 protein. PD related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the system’s 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.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - May 24 2019

Keywords

  • aging
  • dynamic modelling
  • oxidative stress
  • Parkinson’s disease
  • reactive oxygen species
  • Systems biology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Fingerprint Dive into the research topics of 'Design principles of ROS dynamic networks relevant to precision therapies for age-related diseases'. Together they form a unique fingerprint.

Cite this