Abstract
SUMMARYMutations 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.
Highlights
Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene are a major cause of Parkinson’s disease (PD), a common age-dependent neurodegenerative disorder characterized by neuronal damage in multiple brain regions and consequent motor defects (Cookson, 2010)
We used a sequential screening approach consisting of, first, identification of protein-protein interactions for LRRK2, RAB29, BAG5, and GAK; second, classification of the interacting proteins by Gene Ontology (GO); and their functional validation using a LRRK2-relevant assay of recruitment to the trans-Golgi network (TGN) (Figure 1A)
We found that treatment with small interfering RNA (siRNA) against VPS52 decreased LRRK2:RAB29 localization to the TGN, but knockdown of VPS35 or VPS29 had no effect, showing that any interactions between LRRK2, RAB29, and VPS52 are independent of retromer (Figure S4B)
Summary
Mutations in the LRRK2 gene are a major cause of Parkinson’s disease (PD), a common age-dependent neurodegenerative disorder characterized by neuronal damage in multiple brain regions and consequent motor defects (Cookson, 2010). LRRK2 encodes a large protein with multiple protein-protein interaction domains and two enzymatic domains: kinase and GTPase. Multiple lines of evidence suggest that LRRK2 plays some undefined role in the endo-lysosomal system. LRRK2 is present at multiple intracellular membranes (Alegre-Abarrategui et al, 2009; Biskup et al, 2006), possibly related to its ability to bind (Beilina et al, 2014; Dodson et al, 2012; MacLeod et al, 2013) and phosphorylate (Ito et al, 2016; Steger et al, 2016; Thirstrup et al, 2017; Yun et al, 2015) RAB proteins
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call