The Parkinson’s Disease Protein LRRK2 Interacts with the GARP Complex to Promote Retrograde Transport to the trans-Golgi Network

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. [Display omitted] •The Parkinson’s disease kinase LRRK2 interacts with the GARP complex at the TGN•LRRK2 stabilizes the binding of GARP to the t-SNARE Syntaxin-6•LRRK2 regulates retrograde and anterograde transport in a kinase-dependent manner•Depletion of GARP intensifies neurodegeneration in C. elegans expressing G2019S-LRRK2 Mutations in LRRK2 are linked to Parkinson’s disease. However, the cellular role of LRRK2 remains elusive. Using a combination of proteomics and imaging techniques, Beilina et al. describe a function of LRRK2 mediating endosome-TGN transport by scaffolding the GARP:Syntaxin-6 interaction, suggesting a connection between GARP and LRRK2 in Parkinson’s disease.