LRRK 2 localizes to endosomes and interacts with clathrin‐light chains to limit Rac1 activation

Mutations in leucine‐rich repeat kinase 2 ( LRRK 2) are the most common cause of dominant‐inherited Parkinson's disease ( PD ), and yet we do not fully understand the physiological function(s) of LRRK 2. Various components of the clathrin machinery have been recently found mutated in familial forms of PD . Here, we provide molecular insight into the association of LRRK 2 with the clathrin machinery. We report that through its GTP ase domain, LRRK 2 binds directly to clathrin‐light chains ( CLC s). Using genome‐edited HA ‐ LRRK 2 cells, we localize LRRK 2 to endosomes on the degradative pathway, where it partially co‐localizes with CLC s. Knockdown of CLC s and/or LRRK 2 enhances the activation of the small GTP ase Rac1, leading to alterations in cell morphology, including the disruption of neuronal dendritic spines. In Drosphila , a minimal rough eye phenotype caused by overexpression of Rac1, is dramatically enhanced by loss of function of CLC and LRRK 2 homologues, confirming the importance of this pathway in vivo . Our data identify a new pathway in which CLC s function with LRRK 2 to control Rac1 activation on endosomes, providing a new link between the clathrin machinery, the cytoskeleton and PD.