The Parkinson’s Disease Protein LRRK2 Interacts with the GARP Complex to Promote Retrograde Transport to the trans-Golgi Network
Alexandra Beilina,
Luis Bonet-Ponce,
Ravindran Kumaran,
Jennifer J. Kordich,
Morié Ishida,
Adamantios Mamais,
Alice Kaganovich,
Sara Saez-Atienzar,
David C. Gershlick,
Dorien A. Roosen,
Laura Pellegrini,
Vlad Malkov,
Matthew J. Fell,
Kirsten Harvey,
Juan S. Bonifacino,
Darren J. Moore,
Mark R. Cookson
Affiliations
Alexandra Beilina
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA
Luis Bonet-Ponce
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA
Ravindran Kumaran
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA
Jennifer J. Kordich
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA
Morié Ishida
Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA
Adamantios Mamais
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA
Alice Kaganovich
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA
Sara Saez-Atienzar
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA
David C. Gershlick
Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA
Dorien A. Roosen
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA; School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AP, UK
Laura Pellegrini
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA; Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
Vlad Malkov
Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Matthew J. Fell
Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Kirsten Harvey
Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
Juan S. Bonifacino
Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA
Darren J. Moore
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA
Mark R. Cookson
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA; Corresponding author
Summary: Mutations in Leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease (PD). However, the precise function of LRRK2 remains unclear. We report an interaction between LRRK2 and VPS52, a subunit of the Golgi-associated retrograde protein (GARP) complex that identifies a function of LRRK2 in regulating membrane fusion at the trans-Golgi network (TGN). At the TGN, LRRK2 further interacts with the Golgi SNAREs VAMP4 and Syntaxin-6 and acts as a scaffolding platform that stabilizes the GARP-SNAREs complex formation. Therefore, LRRK2 influences both retrograde and post-Golgi trafficking pathways in a manner dependent on its GTP binding and kinase activity. This action is exaggerated by mutations associated with Parkinson’s disease and can be blocked by kinase inhibitors. Disruption of GARP sensitizes dopamine neurons to mutant LRRK2 toxicity in C. elegans, showing that these pathways are interlinked in vivo and suggesting a link in PD.
