Inhibition of the Exocyst Complex Attenuates the LRRK2 Pathological Effects

Pathological mutations in leucine-rich repeat kinase 2 (LRRK2) gene are the major genetic cause of Parkinson's disease (PD). Multiple lines of evidence link LRRK2 to the control of vesicle dynamics through phosphorylation of a subset of RAB proteins. However, the molecular mechanisms underlying these processes are not fully elucidated. We have previously demonstrated that LRRK2 increases the exocyst complex assembly by Sec8 interaction, one of the eight members of the exocyst complex, and that Sec8 over-expression mitigates the LRRK2 pathological effect in PC12 cells. Here, we extend this analysis using LRRK2 drosophila models and show that the LRRK2-dependent exocyst complex assembly increase is downstream of RAB phosphorylation. Moreover, exocyst complex inhibition rescues mutant LRRK2 pathogenic phenotype in cellular and drosophila models. Finally, prolonged exocyst inhibition leads to a significant reduction in the LRRK2 protein level, overall supporting the role of the exocyst complex in the LRRK2 pathway. Taken together, our study suggests that modulation of the exocyst complex may represent a novel therapeutic target for PD.

Automated summary

Pathological mutations in the LRRK2 gene are a major genetic cause of Parkinson's disease (PD), and they are linked to vesicle dynamics control. The study shows that LRRK2 increases the assembly of the exocyst complex through Sec8 interaction, and inhibition of the exocyst complex can rescue the pathogenic phenotype of mutant LRRK2. Prolonged exocyst inhibition leads to a reduction in LRRK2 protein level, supporting the role of the exocyst complex in the LRRK2 pathway.