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LRRK 2 localizes to endosomes and interacts with clathrin‐light chains to limit Rac1 activation
Author(s) -
Schreij Andrea MA,
Chaineau Mathilde,
Ruan Wenjing,
Lin Susan,
Barker Philip A,
Fon Edward A,
McPherson Peter S
Publication year - 2015
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201438714
Subject(s) - endosome , microbiology and biotechnology , rac1 , clathrin , chemistry , immunoglobulin light chain , limit (mathematics) , endocytosis , biophysics , biology , biochemistry , signal transduction , genetics , receptor , antibody , intracellular , mathematical analysis , mathematics
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.