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The Parkinson’s disease protein LRRK2 interacts with the GARP complex to promote retrograde transport to the trans-Golgi network

Beilina, A; Bonet-Ponce, L; Kumaran, R; Kordich, JJ; Ishida, M; Mamais, A; Kaganovich, A; ... Cookson, MR; + view all (2020) The Parkinson’s disease protein LRRK2 interacts with the GARP complex to promote retrograde transport to the trans-Golgi network. Cell Reports , 31 (5) , Article 107614. 10.1016/j.celrep.2020.107614. Green open access

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Abstract

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.

Type: Article
Title: The Parkinson’s disease protein LRRK2 interacts with the GARP complex to promote retrograde transport to the trans-Golgi network
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2020.107614
Publisher version: https://doi.org/10.1016/j.celrep.2020.107614
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Leucine-rich repeat kinase 2, neurodegeneration, membrane trafficking, lysosome, endosome, neurodegenerative disease, VPS52, RAB29, RAB7L1, neuroscience
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10096349
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