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

Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2626-31. doi: 10.1073/pnas.1318306111.

Alexandria Beilina ¹, Iakov N Rudenko, Alice Kaganovich, Laura Civiero, Hien Chau, Suneil K Kalia, Lorraine V Kalia, Evy Lobbestael, Ruth Chia, Kelechi Ndukwe, Jinhui Ding, Mike A Nalls, International Parkinson’s Disease Genomics Consortium, North American Brain Expression Consortium, Maciej Olszewski, David N Hauser, Ravindran Kumaran, Andres M Lozano, Veerle Baekelandt, Lois E Greene, Jean-Marc Taymans, Elisa Greggio, Mark R Cookson

Affiliations

Affiliation

1 Cell Biology and Gene Expression Section, Computational Biology Core, Laboratory of Neurogenetics, and Molecular Genetics Section, National Institute on Aging/National Institutes of Health, Bethesda, MD 20892.

PMID: 24510904 DOI: 10.1073/pnas.1318306111

Abstract

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.

Keywords

BAG5; GAK; autophagy; trans-Golgi.

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