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
  • 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.