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

International Parkinson’s Disease Genomics Consortium

Beilina A., Rudenko I.N., Kaganovich A., Civiero L., Chau H., Kalia S.K., Kalia L.V., Lobbestael E., Chia R., Ndukwe K., Ding J., Nalls M.A., Olszewski M., Hauser D.N., Kumaran R., Lozano A.M., Baekelandt V., Greene L.E., Taymans J.M., Greggio E., Cookson M.R., Nalls M.A., Plagnol V., Hernandez D.G., Sharma M., Sheerin U.M., Saad M., Simon-Sanchez J., Schulte C., Lesage S., Sveinbjornsdottir S., Arepalli S., Barker R., Ben-Shlomo Y., Berendse H.W., Berg D., Bhatia K., de Bie R.M., Biffi A., Bloem B., Bochdanovits Z., Bonin M., Bras J.M., Brockmann K., Brooks J., Burn D.J., Charlesworth G., Chen H., Chinnery P.F., Chong S., Clarke C.E., Cookson M.R., Cooper J.M., Corvol J.C., Counsell C., Damier P., Dartigues J.F., Deloukas P., Deuschl G., Dexter D.T., van Dijk K.D., Dillman A., Durif F., Durr A., Edkins S., Evans J.R., Foltynie T., Gao J., Gardner M., Gibbs J.R., Goate A., Gray E., Guerreiro R., Gustafsson O., Harris C., van Hilten J.J., Hofman A., Hollenbeck A., Holton J., Hu M., Huang X., Huber H., Hudson G., Hunt S.E., Huttenlocher J., Illig T., Jonsson P.V., Lambert J.C., Langford C., Lees A., Lichtner P., Limousin P., Lopez G., Lorenz D., McNeill A., Moorby C., Moore M., Morris H.R., Morrison K.E., Mudanohwo E., O'Sullivan S.S., Pearson J., Perlmutter J.S., Petursson H., Pollak P., Post B., Potter S., Ravina B., Revesz T., Riess O., Rivadeneira F., Rizzu P., Ryten M., Sawcer S., Schapira A., Scheffer H., Shaw K., Shoulson I., Sidransky E., Smith C., Spencer C.C., Stefansson H., Steinberg S., Stockton J.D., Strange A., Talbot K., Tanner C.M., Tashakkori-Ghanbaria A., Tison F., Trabzuni D., Traynor B.J., Uitterlinden A.G., Velseboer D., Vidailhet M., Walker R., van de Warrenburg B., Wickremaratchi M., Williams N., Williams-Gray C.H., Winder-Rhodes S., Stefansson K., Martinez M., Hardy J., Heutink P., Brice A., Gasser T., Singleton A.B., Wood N.W., Arepalli S., Cookson M.R., Dillman A., Ferrucci L., Gibbs J.R., Hernandez D.G., Johnson R., Longo D.L., Majounie E., Nalls M.A., O'Brien R., Singleton A.B., Traynor B.J., Troncoso J., van der Brug M., Zielke H.R., Zonderman A.B.

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.

Proc. Natl. Acad. Sci. U.S.A. 111:2626-2631(2014) [PubMed] [Europe PMC]

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