Tissue specific LRRK2 interactomes reveal a distinct striatal functional unit

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 evaluated taking into consideration the differential expression patterns and the co-expression behaviours of the LRRK2 interactors in 15 different healthy tissue types. 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. The general LRRK2 interactome paired with the expression profiles of its members constitutes a powerful tool to generate tissue-specific LRRK2 interactomes. We exemplified the generation of the tissue-specific LRRK2 interactomes and explored the functions highlighted by the “core LRRK2 interactors” in the striatum in comparison with the cerebellum. Finally, we illustrated how the LRRK2 general interactome reported in this manuscript paired with the expression profiles can be used to trace the relationship between LRRK2 and specific interactors of interest, here focusing on the LRRK2 interactors belonging to the Rab protein family.Author summary: Parkinson’s disease is characterized by the progressive degeneration of the brain (neurodegeneration) involving the brain regions responsible for controlling fine movements. The exact mechanism responsible for Parkinson’s neurodegeneration is still unclear, however different mutations in multiple genes have been associated with the disease. Mutations in the LRRK2 gene constitute a genetic risk factor for both familial and sporadic Parkinson’s disease, suggesting that the LRRK2 protein may play an important role in Parkinson’s. It has been suggested LRRK2 to be a “hub protein”, meaning a protein involved in the orchestration of multiple functions within the cell; functions that are probably activated with regional and temporal specificity. Here, we constructed a computational model centred on LRRK2 by collecting information related to the hundreds of proteins that have been found able to interact with LRRK2 (LRRK2 interactome). This model can be used to simulate LRRK2 functions in different tissues, additionally it can be used to trace specific LRRK2 interactors and follow their behaviour across different tissues. For example, we showed a dichotomy for the LRRK2 interactome expression between the brain and the peripheral tissues; while the brain regions forming the striatum (the structure mostly affected in Parkinson’s) showed a similar functional profile.