Mutations in LRRK2 are associated with risk of Parkinson's disease. James Collins, Benjamin Wolozin and colleagues have now used a systems biology approach to find new regulators of LRRK2 (Hum. Mol. Genet. doi:10.1093/hmg/ddu202, 2 May 2014). They integrated data from 119 publicly available microarray experiments using RNA from the brain and blood of individuals with Parkinson's disease and controls to build a coexpression network centered on LRRK2 that confirmed known interactions and predicted many new regulators. To validate these predictions, the authors targeted 181 Caenorhabditis elegans genes and 200 human genes (corresponding to 506 putative C. elegans orthologs) exhibiting LRRK2-coordinated expression using RNA interference (RNAi) in worms expressing human LRRK2. They found that 40% of the genes affected neurite shortening and dopaminergic neuron toxicity, phenotypes associated with LRRK2-driven Parkinson's disease. They further identified RGS2 as a regulatory hub in the network and confirmed that RGS2 physically interacted with LRRK2 in vitro and in vivo. They also found that RGS2 interacted synergistically with LRRK2 to inhibit its kinase activity. Finally, they found that Parkinson's disease cases with the common LRRK2 Gly2019Ser alteration, as well as sporadic cases, had lower levels of RGS2 protein in caudate striatal tissue compared to controls.