title: LRRK2 localizes to endosomes and interacts with clathrin-light chains to limit Rac1 activation.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of dominant-inherited Parkinson's disease (PD), and yet we do not fully understand the physiological function(s) of LRRK2. 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 LRRK2 with the clathrin machinery. We report that through its GTPase domain, LRRK2 binds directly to clathrin-light chains (CLCs). Using genome-edited HA-LRRK2 cells, we localize LRRK2 to endosomes on the degradative pathway, where it partially co-localizes with CLCs. Knockdown of CLCs and/or LRRK2 enhances the activation of the small GTPase 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 LRRK2 homologues, confirming the importance of this pathway in vivo. Our data identify a new pathway in which CLCs function with LRRK2 to control Rac1 activation on endosomes, providing a new link between the clathrin machinery, the cytoskeleton and PD.
authors.affiliation: Department of Neurology and Neurosurgery and McGill Parkinson Program, Montreal Neurological Institute McGill University, Montreal, Quebec, Canada.
authors.forename: Andrea M A
authors.initials: AM
authors.lastname: Schreij
authors.affiliation: Department of Neurology and Neurosurgery and McGill Parkinson Program, Montreal Neurological Institute McGill University, Montreal, Quebec, Canada.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Chaineau
authors.affiliation: Department of Neurology and Neurosurgery and McGill Parkinson Program, Montreal Neurological Institute McGill University, Montreal, Quebec, Canada.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Ruan
authors.affiliation: Department of Neurology and Neurosurgery and McGill Parkinson Program, Montreal Neurological Institute McGill University, Montreal, Quebec, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Neurology and Neurosurgery and McGill Parkinson Program, Montreal Neurological Institute McGill University, Montreal, Quebec, Canada.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Barker
authors.affiliation: Department of Neurology and Neurosurgery and McGill Parkinson Program, Montreal Neurological Institute McGill University, Montreal, Quebec, Canada ted.fon@mcgill.ca peter.mcpherson@mcgill.ca.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fon
authors.affiliation: Department of Neurology and Neurosurgery and McGill Parkinson Program, Montreal Neurological Institute McGill University, Montreal, Quebec, Canada ted.fon@mcgill.ca peter.mcpherson@mcgill.ca.
authors.forename: Peter S
authors.initials: PS
authors.lastname: McPherson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001921:Brain / Q000166:cytology / Q000378:metabolism; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D033941:Clathrin Light Chains / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics; D011992:Endosomes / Q000378:metabolism*; D005123:Eye / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D033941:Clathrin Light Chains; D029721:Drosophila Proteins; C107953:RAC1 protein, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein
keywords: Drosophila melanogaster; Parkinson's disease; Rac1; clathrin; endosomes