Journal
CELL REPORTS
Volume 31, Issue 5, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.107614
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Funding
- Intramural Research Program of the NIH, National Institute on Aging
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- NIH [R01 NS091719]
- University College London (UCL)
- Microscopy & Imaging Core, NICHD, NIH
- [MR/M00676X/1]
- MRC [MR/M00676X/1] Funding Source: UKRI
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [ZIAHD001607] Funding Source: NIH RePORTER
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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.
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