title: Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease.
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.
authors: 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.
authors: Alexandria
authors: A
authors: Beilina
authors: Iakov N
authors: IN
authors: Rudenko
authors: Alice
authors: A
authors: Kaganovich
authors: Laura
authors: L
authors: Civiero
authors: Hien
authors: H
authors: Chau
authors: Suneil K
authors: SK
authors: Kalia
authors: Lorraine V
authors: LV
authors: Kalia
authors: Evy
authors: E
authors: Lobbestael
authors: Ruth
authors: R
authors: Chia
authors: Kelechi
authors: K
authors: Ndukwe
authors: Jinhui
authors: J
authors: Ding
authors: Mike A
authors: MA
authors: Nalls
authors: Maciej
authors: M
authors: Olszewski
authors: David N
authors: DN
authors: Hauser
authors: Ravindran
authors: R
authors: Kumaran
authors: Andres M
authors: AM
authors: Lozano
authors: Veerle
authors: V
authors: Baekelandt
authors: Lois E
authors: LE
authors: Greene
authors: Jean-Marc
authors: JM
authors: Taymans
authors: Elisa
authors: E
authors: Greggio
authors: Mark R
authors: MR
authors: Cookson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000704:Analysis of Variance; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002458:Cell Fractionation; D017931:DNA Primers / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006056:Golgi Apparatus / Q000648:ultrastructure; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology*; D010957:Plasmids / Q000235:genetics; D025941:Protein Interaction Mapping / Q000379:methods*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D022161:Transport Vesicles / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C496515:BAG5 protein, human; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C486325:GAK protein, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins
keywords: BAG5; GAK; autophagy; trans-Golgi