LRRK2 Modulates the Exocyst Complex Assembly by Interacting with Sec8

Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson’s disease
(PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown.
However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle
trafficking, likely by Rab phosphorylation, that in turn may regulate different aspects of neuronal
physiology. Here we show that LRRK2 interacts with Sec8, one of eight subunits of the exocyst
complex. The exocyst complex is an evolutionarily conserved multisubunit protein complex mainly
involved in tethering secretory vesicles to the plasma membrane and implicated in the regulation
of multiple biological processes modulated by vesicle trafficking. Interestingly, Rabs and exocyst
complex belong to the same protein network. Our experimental evidence indicates that LRRK2
kinase activity or the presence of the LRRK2 kinase domain regulate the assembly of exocyst
subunits and that the over‐expression of Sec8 significantly rescues the LRRK2 G2019S mutant
pathological effect. Our findings strongly suggest an interesting molecular mechanism by which
LRRK2 could modulate vesicle trafficking and may have important implications to decode the
complex role that LRRK2 plays in neuronal physiology.