Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

被引：277

作者：

Beilina, Alexandria ^{[1
]}

Rudenko, Iakov N. ^{[1
]}

Kaganovich, Alice ^{[1
]}

Civiero, Laura ^{[4
]}

Chau, Hien ^{[5
]}

Kalia, Suneil K. ^{[6
]}

Kalia, Lorraine V. ^{[7
]}

Lobbestael, Evy ^{[8
]}

Chi, Ruth ^{[1
]}

Ndukwe, Kelechi ^{[1
]}

Ding, Jinhui ^{[2
]}

Nalls, Mike A. ^{[3
]}

Olszewski, Maciej ^{[9
]}

Hauser, David N. ^{[1
]}

Kumaran, Ravindran ^{[1
]}

Lozano, Andres M. ^{[6
]}

Baekelandt, Veerle ^{[8
]}

Greene, Lois E. ^{[9
]}

Taymans, Jean-Marc ^{[8
]}

Greggio, Elisa ^{[4
]}

Cookson, Mark R. ^{[1
]}

机构：

[1] NIA, Computat Biol Core, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[2] NIA, Mol Genet Sect, NIH, Bethesda, MD 20892 USA

[3] Univ Padua, Dept Biol, I-35131 Padua, Italy

[4] Univ Toronto, Univ Hlth Network, Toronto Western Res Inst, Div Brain Imaging & Behav Syst Neurosci, Toronto, ON M5T 2S8, Canada

[5] Univ Toronto, Univ Hlth Network, Toronto Western Res Inst, Dept Surg,Div Neurosurg, Toronto, ON M5T 2S8, Canada

[6] Univ Toronto, Univ Hlth Network, Toronto Western Res Inst, Dept Med,Div Neurosurg, Toronto, ON M5T 2S8, Canada

[7] Katholieke Univ Leuven, Lab Neurobiol & Gene Therapy, B-3000 Louvain, Belgium

[8] NHLBI, Lab Cellular Physiol, NIH, Bethesda, MD 20892 USA

[9] Brown Univ, NIH, Grad Partnership Program, Dept Neurosci, Providence, RI 02912 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2014年 / 111卷 / 07期

基金：

美国国家卫生研究院;

关键词：

BAG5; GAK; trans-Golgi; autophagy; LRRK2; RECRUITMENT; AUTOPHAGY; VARIANTS; CLATHRIN; SEQUENCE; PROTEIN;

D O I：

10.1073/pnas.1318306111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson disease (PD), and common variants around LRRK2 are a risk factor for sporadic PD. Using protein-protein interaction arrays, we identified BCL2-associated athanogene 5, Rab7L1 (RAB7, member RAS oncogene family-like 1), and Cyclin-G-associated kinase as binding partners of LRRK2. The latter two genes are candidate genes for risk for sporadic PD identified by genome-wide association studies. These proteins form a complex that promotes clearance of Golgi-derived vesicles through the autophagy-lysosome system both in vitro and in vivo. We propose that three different genes for PD have a common biological function. More generally, data integration from multiple unbiased screens can provide insight into human disease mechanisms.

引用

页码：2626 / 2631

页数：6

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