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

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease
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.
0027-8424
2626-2631
Beilina, A.
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Rudenko, I.N.
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Kaganovich, A.
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Civiero, L.
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Chau, H.
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Kalia, S.K.
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Kalia, L.V.
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Lobbestael, E.
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Chia, R.
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Ndukwe, K.
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Ding, J.
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Nalls, M.A.
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Olszewski, M.
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Hauser, D.N.
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Kumaran, R.
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Lozano, A.M.
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Baekelandt, V.
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Greene, L.E.
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Taymans, J.-M.
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Greggio, E.
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Cookson, M.R.
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Plagnol, V.
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Martinez, M.
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Hernandez, D.G.
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Sharma, M.
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Sheerin, U.-M.
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Saad, M.
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Simon-Sanchez, J.
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Schulte, C.
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Lesage, S.
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Sveinbjornsdottir, S.
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Arepalli, S.
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Barker, R.
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Ben-Shlomo, Y.
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Berendse, H.W.
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Berg, D.
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Bhatia, K.
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de Bie, R.M.A.
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Biffi, A.
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Bloem, B.
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Bochdanovits, Z.
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Bonin, M.
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Bras, J.M.
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Brockmann, K.
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Brooks, J.
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Burn, D.J.
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Charlesworth, G.
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Chen, H.
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Chong, S.
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Clarke, C.E.
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Cooper, J.M.
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Corvol, J.C.
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Counsell, C.
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Damier, P.
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Dartigues, J.-F.
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Deloukas, P.
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Deuschl, G.
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Dexter, D.T.
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van Dijk, K.D.
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Dillman, A.
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Durr, A.
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Edkins, S.
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Evans, J.R.
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Foltynie, T.
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Gao, J.
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Gardner, M.
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Gibbs, J.R.
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Goate, A.
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Gray, E.
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Guerreiro, R.
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Gustafsson, O.
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Harris, C.
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van Hilten, J.J.
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Hofman, A.
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Hollenbeck, A.
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Holton, J.
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Hu, M.
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Huang, X.
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Huber, H.
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Hudson, G.
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Hunt, S.E.
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Huttenlocher, J.
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Illig, T.
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Munchen, H.Z.
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Jonsson, P.V.
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Lambert, J.-C.
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Langford, C.
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Lees, A.
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Lichtner, P.
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Limousin, P.
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Lopez, G.
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Lorenz, D.
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McNeill, A.
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Moorby, C.
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Moore, M.
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Morris, H.R.
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Morrison, K.E.
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Mudanohwo, E.
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O'Sullivan, S.S.
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Pearson, J.
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Perlmutter, J.S.
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Petursson, H.
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Pollak, P.
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Post, B.
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Potter, S.
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Ravina, B.
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Revesz, T.
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Riess, O.
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Rivadeneira, F.
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Rizzu, P.
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Ryten, M.
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Schapira, A.
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Scheffer, H.
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Shaw, K.
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Shoulson, I.
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Smith, C.
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Talbot, K.
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van de Warrenburg, B.
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Hardy, J.
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Gasser, T.
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Singleton, A.B.
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Wood, N.W.
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Chinnery, P.F.
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Ferrucci, L.
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Johnson, R.
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Longo, D.L.
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Majounie, E.
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O'Brien, R.
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van der Brug, M.
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Beilina, A.
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Civiero, L.
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Kalia, L.V.
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Lobbestael, E.
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Chia, R.
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Ding, J.
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Olszewski, M.
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Hauser, D.N.
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Kumaran, R.
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Lozano, A.M.
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Baekelandt, V.
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Greene, L.E.
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Cookson, M.R.
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Plagnol, V.
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Martinez, M.
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Sharma, M.
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Sheerin, U.-M.
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Saad, M.
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Simon-Sanchez, J.
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Schulte, C.
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Lesage, S.
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Arepalli, S.
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Ben-Shlomo, Y.
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Berg, D.
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Bhatia, K.
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de Bie, R.M.A.
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Bloem, B.
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Bras, J.M.
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Brockmann, K.
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Brooks, J.
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Burn, D.J.
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Charlesworth, G.
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Chen, H.
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Chong, S.
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Clarke, C.E.
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Cooper, J.M.
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Corvol, J.C.
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Counsell, C.
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Damier, P.
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Dartigues, J.-F.
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Deloukas, P.
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Deuschl, G.
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Dexter, D.T.
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van Dijk, K.D.
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Dillman, A.
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Durif, F.
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Durr, A.
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Edkins, S.
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Evans, J.R.
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Foltynie, T.
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Gao, J.
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Gardner, M.
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Gibbs, J.R.
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Goate, A.
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Gray, E.
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Guerreiro, R.
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Smith, C.
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Spencer, C.C.A.
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Stefansson, H.
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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., Plagnol, V., Martinez, M., 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.A., Biffi, A., Bloem, B., Bochdanovits, Z., Bonin, M., Bras, J.M., Brockmann, K., Brooks, J., Burn, D.J., Charlesworth, G., Chen, H., Chong, S., Clarke, C.E., 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., Munchen, H.Z., 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.A., 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., Hardy, J., Heutink, P., Brice, A., Gasser, T., Singleton, A.B., Wood, N.W., Chinnery, P.F., Ferrucci, L., Johnson, R., Longo, D.L., Majounie, E., O'Brien, R., Troncoso, J., van der Brug, M., Zielke, H.R. and Zonderman, A.B. (2014) Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proceedings of the National Academy of Sciences, 111 (7), 2626-2631. (doi:10.1073/pnas.1318306111). (PMID:24510904)

Record type: Article

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.

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More information

Accepted/In Press date: 20 December 2013
Published date: 18 February 2014
Organisations: Medical Education

Identifiers

Local EPrints ID: 398324
URI: http://eprints.soton.ac.uk/id/eprint/398324
DOI: doi:10.1073/pnas.1318306111
ISSN: 0027-8424
PURE UUID: 356ea203-99be-417e-b6c1-c0435496ea79
ORCID for K.E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 21 Jul 2016 13:45
Last modified: 15 Mar 2024 01:32

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Contributors

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

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