Transcriptomics analyses of the LRRK2 protein interactome reveal distinct molecular signatures for sporadic and LRRK2 Parkinson's Disease

Abstract

Mutations in the LRRK2 gene are the most common genetic cause for familial Parkinsons Disease (LRRK2-PD) and an important risk factor for sporadic PD (sPD). Multiple clinical trials are ongoing to evaluate the benefits associated with the therapeutical reduction of LRRK2 kinase activity. In this study, we described the changes on transcriptomic profiles (whole blood mRNA levels) of LRRK2 protein interactors in the sPD and LRRK2-PD cases as compared to healthy controls with the aim of comparing the two PD conditions. We went on to model the protein-protein interaction (PPI) network around LRRK2, which was weighted to reflect the transcriptomic changes in the network based on the expression and co-expression levels. Our results showed that LRRK2 interactors present both similar but also different alterations in expression levels and co-expression behaviours in the sPD and LRRK2-PD cases. The similar changes result in decreased connectivity within a topological cluster of the LRRK2 PPI network associated with ribosomal functions and DNA/RNA metabolism in both the sPD and LRRK2-PD scenario; while the connectivity within the autophagy/mitophagy/neurotransmitter-transport related cluster was increased exclusively in the LRRK2-PD condition as compared to the healthy controls. These results suggest that, albeit being classified as the same disease based on clinical features, LRRK2-PD and sPD show some significant differences from a molecular perspective.