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

Alexandria Beilina; Iakov N Rudenko; Alice Kaganovich; Laura Civiero; Hien Chau; Suneil K Kalia; Lorraine V Kalia; Evy Lobbestael; Ruth Chia; Kelechi Ndukwe; Jinhui Ding; Mike A Nalls; Maciej Olszewski; David N Hauser; Ravindran Kumaran; Andres M Lozano; Veerle Baekelandt; Lois E Greene; Jean-Marc Taymans; Elisa Greggio; Mark R Cookson; International Parkinson's Disease Genomics Consortium (IPDGC); Karen Morrison

doi:10.1073/pnas.1318306111

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

Alexandria Beilina, Iakov N Rudenko, Alice Kaganovich, Laura Civiero, Hien Chau, Suneil K Kalia, Lorraine V Kalia, Evy Lobbestael, Ruth Chia, Kelechi Ndukwe, Jinhui Ding, Mike A Nalls, Maciej Olszewski, David N Hauser, Ravindran Kumaran, Andres M Lozano, Veerle Baekelandt, Lois E Greene, Jean-Marc Taymans, Elisa GreggioMark R Cookson, International Parkinson's Disease Genomics Consortium (IPDGC), Karen Morrison

Research output: Contribution to journal › Article › peer-review

231 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2626-31
Number of pages	6
Journal	National Academy of Sciences. Proceedings
Volume	111
Issue number	7
DOIs	https://doi.org/10.1073/pnas.1318306111
Publication status	Published - 18 Feb 2014

Keywords

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
Mass Spectrometry
Microscopy, Confocal
Multiprotein Complexes
Parkinson Disease
Plasmids
Protein Interaction Mapping
Protein-Serine-Threonine Kinases
Transport Vesicles
rab GTP-Binding Proteins

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1318306111

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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., ... Morrison, K. (2014). Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. National Academy of Sciences. Proceedings, 111(7), 2626-31. https://doi.org/10.1073/pnas.1318306111

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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.",

keywords = "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, Mass Spectrometry, Microscopy, Confocal, Multiprotein Complexes, Parkinson Disease, Plasmids, Protein Interaction Mapping, Protein-Serine-Threonine Kinases, Transport Vesicles, rab GTP-Binding Proteins",

author = "Alexandria Beilina and Rudenko, {Iakov N} and Alice Kaganovich and Laura Civiero and Hien Chau and Kalia, {Suneil K} and Kalia, {Lorraine V} and Evy Lobbestael and Ruth Chia and Kelechi Ndukwe and Jinhui Ding and Nalls, {Mike A} and Maciej Olszewski and Hauser, {David N} and Ravindran Kumaran and Lozano, {Andres M} and Veerle Baekelandt and Greene, {Lois E} and Jean-Marc Taymans and Elisa Greggio and Cookson, {Mark R} and {International Parkinson's Disease Genomics Consortium (IPDGC)} and Karen Morrison",

year = "2014",

month = feb,

day = "18",

doi = "10.1073/pnas.1318306111",

language = "English",

volume = "111",

pages = "2626--31",

journal = "National Academy of Sciences. Proceedings",

issn = "1091-6490",

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Beilina, A, Rudenko, IN, Kaganovich, A, Civiero, L, Chau, H, Kalia, SK, Kalia, LV, Lobbestael, E, Chia, R, Ndukwe, K, Ding, J, Nalls, MA, Olszewski, M, Hauser, DN, Kumaran, R, Lozano, AM, Baekelandt, V, Greene, LE, Taymans, J-M, Greggio, E, Cookson, MR, International Parkinson's Disease Genomics Consortium (IPDGC) & Morrison, K 2014, 'Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease', National Academy of Sciences. Proceedings, vol. 111, no. 7, pp. 2626-31. https://doi.org/10.1073/pnas.1318306111

TY - JOUR

T1 - Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

AU - Beilina, Alexandria

AU - Rudenko, Iakov N

AU - Kaganovich, Alice

AU - Civiero, Laura

AU - Chau, Hien

AU - Kalia, Suneil K

AU - Kalia, Lorraine V

AU - Lobbestael, Evy

AU - Chia, Ruth

AU - Ndukwe, Kelechi

AU - Ding, Jinhui

AU - Nalls, Mike A

AU - Olszewski, Maciej

AU - Hauser, David N

AU - Kumaran, Ravindran

AU - Lozano, Andres M

AU - Baekelandt, Veerle

AU - Greene, Lois E

AU - Taymans, Jean-Marc

AU - Greggio, Elisa

AU - Cookson, Mark R

AU - International Parkinson's Disease Genomics Consortium (IPDGC)

AU - Morrison, Karen

PY - 2014/2/18

Y1 - 2014/2/18

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Analysis of Variance

KW - Blotting, Western

KW - Brain

KW - Cell Fractionation

KW - DNA Primers

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Golgi Apparatus

KW - HEK293 Cells

KW - Humans

KW - Immunoprecipitation

KW - Intracellular Signaling Peptides and Proteins

KW - Mass Spectrometry

KW - Microscopy, Confocal

KW - Multiprotein Complexes

KW - Parkinson Disease

KW - Plasmids

KW - Protein Interaction Mapping

KW - Protein-Serine-Threonine Kinases

KW - Transport Vesicles

KW - rab GTP-Binding Proteins

U2 - 10.1073/pnas.1318306111

DO - 10.1073/pnas.1318306111

M3 - Article

C2 - 24510904

SN - 1091-6490

VL - 111

SP - 2626

EP - 2631

JO - National Academy of Sciences. Proceedings

JF - National Academy of Sciences. Proceedings

IS - 7

ER -

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

Abstract

Keywords

UN SDGs

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