Figure 1

Experimental design. (A) The starting material was a manually curated list of key proteins clustered in motives that allowed construction of condition-specific networks for neurodegeneration after RA and for neuroprotection after DA. Using TPMS, network static maps were converted into topological maps associated with mathematical equations. The available data from unbiased proteomic analysis generated from RA and DA models (Casas et al., 2015) was used to build a set of restrictions collated into a truth table with which all models generated had to comply. Drug screening in silico was used to perturb the neurodegeneration-associated mathematical model and drug combinations that approximated the model to the neuroprotective state were identified. The algorithms used also allowed specification of key proteins involved in the mode of action (MoA) of each drug combination. Finally, we validated new combinations for its neuroprotective effect and putative MoA in vivo and in vitro. (B) Snapshots of the full protein networks associated with the neurodegenerative condition after RA (left, 3,836 nodes, average links per node 13.4) and with the neuroprotective condition after DA (right, 3,296 nodes, average links per node 13.9) visualized through the Cytoscape software platform⁶². Seed proteins for different motives are labelled by colour as indicated. Some seeds belong to more than one motive. (C) List of potential neuroprotective drug combinations identified using the in silico screen.