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

Alexandria Beilina, 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, Maciej Olszewski, David N Hauser, Ravindran Kumaran, Andres M Lozano, Veerle Baekelandt, Lois E Greene, Jean-Marc Taymans, Elisa GreggioMark R Cookson, Pálmi V Jónsson

Research output: Contribution to journalArticlepeer-review

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.

Other keywords

  • Parkinsonsveiki
  • Adaptor Proteins, Signal Transducing
  • Analysis of Variance
  • Blotting, Western
  • Brain
  • Cell Fractionation
  • DNA Primers
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Golgi Apparatus
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins
  • Mass Spectrometry
  • Microscopy, Confocal
  • Multiprotein Complexes
  • Parkinson Disease
  • Plasmids
  • Protein Interaction Mapping
  • Protein-Serine-Threonine Kinases
  • Transport Vesicles
  • rab GTP-Binding Proteins

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