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

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.
Mesh Terms:
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, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Mass Spectrometry, Microscopy, Confocal, Multiprotein Complexes, Parkinson Disease, Plasmids, Protein Interaction Mapping, Protein-Serine-Threonine Kinases, Transport Vesicles, rab GTP-Binding Proteins
Proc. Natl. Acad. Sci. U.S.A.
Date: Feb. 18, 2014
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