Journal Article

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

Rudenko, Iakov N., Nalls, Mike A., Civiero, Laura, Greene, Lois E., Olszewski, Maciej, Lozano, Andres M., Ding, Jinhui, Lobbestael, Evy, Beilina, Alexandria, Kalia, Suneil K., Kumaran, Ravindran, Chia, Ruth, Baekelandt, Veerle, Cookson, Mark R., Taymans, Jean-Marc, Chau, Hien, Kalia, Lorraine V., Ndukwe, Kelechi, Greggio, Elisa, Kaganovich, Alice, Hauser, David N.

2014

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adaptor Proteins, Signal Transducing - metabolism / Analysis of Variance / Autophagy / Biological Sciences / Blotting, Western / Brain - metabolism / Cell Fractionation / Disease risk / DNA Primers - genetics / Gene expression regulation / Genes / Genetic loci / Genetic Loci - genetics / Genetic mutation / Genetic Predisposition to Disease - genetics / genome-wide association study / Genome-Wide Association Study - methods / Golgi Apparatus - ultrastructure / HEK293 Cells / human diseases / Humans / Immunoprecipitation / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Mass Spectrometry / Medical genetics / Microscopy, Confocal / Multiprotein Complexes - genetics / Multiprotein Complexes - metabolism / Mutation / Neurites / Neurons / oncogenes / Parkinson disease / Parkinson Disease - enzymology / Parkinson's disease / Plasmids - genetics / Protein Interaction Mapping - methods / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / protein-protein interactions / Proteins / rab GTP-Binding Proteins - metabolism / rab7 GTP-Binding Proteins / Risk factors / Transfection / Transport Vesicles - metabolism