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

被引：50

作者：

Beilina, Alexandra ^{[1
]}

Bonet-Ponce, Luis ^{[1
]}

Kumaran, Ravindran ^{[1
]}

Kordich, Jennifer J. ^{[2
]}

Ishida, Morie ^{[3
]}

Mamais, Adamantios ^{[1
]}

Kaganovich, Alice ^{[1
]}

Saez-Atienzar, Sara ^{[1
]}

Gershlick, David C. ^{[3
]}

Roosen, Dorien A. ^{[1
,4
]}

Pellegrini, Laura ^{[1
,5
]}

Malkov, Vlad ^{[6
]}

Fell, Matthew J. ^{[6
]}

Harvey, Kirsten ^{[5
]}

Bonifacino, Juan S. ^{[3
]}

Moore, Darren J. ^{[2
]}

Cookson, Mark R. ^{[1
]}

机构：

[1] NIA, Lab Neurogenet, NIH, Bethesda, MD 20814 USA

[2] Van Andel Res Inst, Ctr Neurodegenerat Sci, Grand Rapids, MI 49503 USA

[3] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20814 USA

[4] Univ Reading, Sch Pharm, Reading RG6 6AP, Berks, England

[5] UCL, UCL Sch Pharm, Dept Pharmacol, 29-39 Brunswick Sq, London WC1N 1AX, England

[6] Merck & Co Inc, 33 Ave Louis Pasteur, Boston, MA 02115 USA

来源：

CELL REPORTS | 2020年 / 31卷 / 05期

基金：

英国医学研究理事会;

关键词：

KINASE; 2; LRRK2; ALPHA-SYNUCLEIN; R1441C MUTATION; CATHEPSIN-D; ENDOSOME; DEGRADATION; NEURODEGENERATION; DYSFUNCTION; ASSOCIATION; INHIBITORS;

D O I：

10.1016/j.celrep.2020.107614

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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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页数：20

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