LRRK2/LRRK1 interactions modulate Rab7 activity and inhibit lysosomal exocytosis

Abstract Mutations in the LRRK2 gene are the most common genetic cause of both familial and sporadic Parkinson’s disease (PD). LRRK2 belongs to the leucine-rich repeat kinase (LRRK) family. Two members of the LRRK family exist in humans (LRRK1 and LRRK2). Although there is strong structural similarity between the two proteins, they have attracted very different levels of attention by the scientific community owing to the strong association between LRRK2 and PD. In contrast, the role of LRRK1 is relatively unexplored. LRRK2 is also known to regulate endolysosomal function, but its precise role in this process remains incompletely understood. Our study investigated the interaction between LRRK1 and LRRK2 under different cellular conditions, uncovering their role in modulating the endolysosomal system. We found that LRRK1 and LRRK2 interact and modulate each other’s activity, and that this interaction is reduced under starvation conditions. We also found that LRRK1 and LRRK2 have contrasting effects on lysosomal size, impacting on lysosomal exocytosis. Together, our findings suggest that LRRK2 regulates endolysosomal homeostasis, at least in part, by modulating LRRK1. Our findings offer new insight into the molecular mechanisms associated with lysosomal function and, ultimately, we anticipate this knowledge will help us better understand the molecular crosstalk between LRRK kinases and their contribution to PD pathogenesis. Graphical abstract Starvation reduces the interaction between LRRK2 and LRRK1 due to a conformational change in LRRK2. Under normal conditions, LRRK2/LRRK1 interaction enhances LRRK1 activity, leading to increased phosphorylation of Rab7. Disruption of the Rab7 cycle impairs lysosomal homeostasis, leading to lysosomal accumulation and an increase in lysosomal diameter. This enlargement negatively impacts lysosomal exocytosis. Created with BioRender.com .