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. Epub 2014 Feb 7.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Analysis of Variance
  • Blotting, Western
  • Brain / metabolism
  • Cell Fractionation
  • DNA Primers / genetics
  • Genetic Loci / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods
  • Golgi Apparatus / ultrastructure
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mass Spectrometry
  • Microscopy, Confocal
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Parkinson Disease / enzymology*
  • Plasmids / genetics
  • Protein Interaction Mapping / methods*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Transport Vesicles / metabolism
  • rab GTP-Binding Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • BAG5 protein, human
  • DNA Primers
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • rab7 protein
  • GAK protein, human
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases
  • rab GTP-Binding Proteins