Tissue specific LRRK2 interactomes reveal a distinct functional unit within the striatum

Mutations in LRRK2 are the most common genetic cause of Parkinson’s disease. Despite substantial research efforts, the physiological and pathological role of this multidomain protein remains poorly defined. In this study, we used a systematic approach to construct the general protein-protein interactome around LRRK2, which was then differentiated into 15 tissue-specific interactomes taking into consideration the differential expression patterns and the co-expression behaviours of the LRRK2 interactors in different healthy tissues. The LRRK2 interactors exhibited distinct expression features in the brain as compared to the peripheral tissues analysed. Moreover, a high degree of similarity was found for the LRRK2 interactors in putamen, caudate and nucleus accumbens, thus defining a potential LRRK2 functional cluster within the striatum. We also explored the functions highlighted by the “core LRRK2 interactors” within each tissue and illustrated how the LRRK2 interactomes can be used as a tool to trace the relationship between LRRK2 and specific interactors of interest, here exemplified with a study focused on the LRRK2 interactors belonging to the Rab protein family.