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

Beilina, Alexandra; Rudenko, Iakov N.; Kaganovich, Alice; Civiero, Laura; Chau, Hien; Kalia, Suneil K.; Kalia, Lorraine V.; Lobbestael, Evy; Chia, Ruth; Ndukwe, Kelechi; Ding, Jinhui; Nalls, Michael A.; Olszewski, Maciej B.; Hauser, David N.; Kumaran, R. Ileng; Lozano, Andrés M.; Baekelandt, Veerle; Greene, Lois E.; Taymans, Jean-Marc; Greggio, Elisa; Cookson, Mark; Plagnol, Vincent; Martínez, María; Hernandez, Dena G.; Sharma, Manu; Sheerin, Una Marie; Saad, Mohamad; Simón‐Sánchez, Javier; Schulte, Claudia; Lesage, Suzanne; Sveinbjörnsdóttir, Sigurlaug; Arepalli, Sampath; Barker, RA; Ben‐Shlomo, Yoav; Berendse, H.W.; Berg, Daniela; Bhatia, Kailash P.; Bie, Rob M.A. de; Biffi, Alessandro; Bloem, B.R.; Bochdanovits, Zoltán; Bonin, Michael; Brás, José; Brockmann, Kathrin; Brooks, Janet; Burn, David; Charlesworth, Gavin; Chen, H.; Chong, Siow‐Ann; Clarke, Carl E; Cooper, Jane; Corvol, Jean‐Christophe; Counsell, Carl; Damier, Philippe; Jf, Dartigues; Deloukas, Panos; Deuschl, Günther; Dexter, David T.; Dijk, Karin D. van; Dillman, Allissa; Durif, F.; Dürr, Alexandra; Edkins, Sarah; Evans, Jonathan; Foltynie, Thomas; Gao, Jianjun; Gardner, Michelle; Gibbs, J. Raphael; Goate, Alison; Gray, Emma; Guerreiro, Rita; Gústafsson, Ómar; Harris, Curtis C.; Hilten, Jacobus J. van; Hofman, Albert; Hollenbeck, Albert R.; Holton, Janice L.; Hu, Ming; Huang, Xuemei; Huber, Heiko; Hudson, Gavin; Hunt, Adrienne; Huttenlocher, Johanna; Illig, Thomas; München, Helmholtz Zentrum; Jónsson, Pálmi V.; Lambert, J-C; Langford, Cordelia; Lees, Andrew J.; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; McNeill, Alisdair; Moorby, Catriona D.; Moore, Matthew; Morris, Huw; Morrison, Karen; Mudanohwo, Ese; O’Sullivan, Sean S.; Pearson, Justin; Perlmutter, Joel S.; Pétursson, Hannes; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Révész, Tamás; Rieß, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Sawcer, Stephen; Schapira, Anthony H.V.; Scheffer, Hans; Shaw, Kelly A.; Shoulson, Ira; Sidransky, Ellen; Smith, Callum; Spencer, Chris C. A.; Stefánsson, Hreinn; Steinberg, Stacy; Stockton, Joanne; Strange, Amy; Talbot, Kevin; Tanner, Caroline M.; Tashakkori-Ghanbaria, Avazeh; Tison, François; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, André G.; Velseboer, Daan C.; Vidailhet, Marie; Walker, Robert; Warrenburg, Bart van de; Wickremaratchi, Mirdhu; Williams, Nigel; Williams‐Gray, Caroline H.; Winder‐Rhodes, Sophie; Stefánsson, Kāri; Hardy, John; Heutink, Peter; Brice, Alexis; Gasser, Thomas; Singleton, Andrew B.; Wood, Nicholas W.; Chinnery, Patrick F.; Ferrucci, Luigi; Johnson, Rebecca; Longo, Dan L.; Majounie, Elisa; O’Brien, Richard M.; Troncoso, Juan C.; Brug, Marcel van der; Zielke, H. Ronald; Zonderman, Alan B.

doi:10.1073/pnas.1318306111

Cited by 334 publications

(412 citation statements)

References 41 publications

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“…Subsequently, Rab7 was found in complex with LRRK2 to cooperatively promote clearance of Golgi‐derived vesicles through the autophagy–lysosomal system. The pathogenic mutations, G2019S , R1441C and Y1699C enhanced Golgi clearance, but the hypothesis‐testing mutations that decrease GTP binding, the T1348N, or the kinase‐inactive K1906M, did not sustain Golgi clearance, suggesting that both kinase and GTPase activities are required for maintaining this cellular process 118. Overexpression of VPS35 exhibited protective effects in mutant LRRK2 Drosophila 132; it is of interest to note that mutations in the VPS35 encoding gene have been identified in PD families 133, 134, further implicating the disruption of retromer mediated protein sorting as potentially leading to PD.…”

Section: Lrrk2 Function In Vesicle Dynamics and Retromer Functionmentioning

confidence: 96%

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Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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Section: Lrrk2 Function In Vesicle Dynamics and Retromer Functionmentioning

confidence: 96%

“…130 and Beilina et al . 118 showed a genetic interaction between LRRK2 and Rab7L1; a genetic risk factor for sporadic PD. Expression of G2019S ‐LRRK2 in primary neurons induced lysosomal swelling and accumulation of a component of the retromer complex; the mannose phosphate receptor 130.…”

Section: Lrrk2 Function In Vesicle Dynamics and Retromer Functionmentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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“…Therefore, despite these mutations having a loss of GTPase function, they likely result in a persistent function compared with wild-type protein. [151]). Many pathogenic mechanisms have been reported for LRRK2 mutations.…”

Section: Roc-cor Bidomain Mutationsmentioning

confidence: 99%

“…Many pathogenic mechanisms have been reported for LRRK2 mutations. Among those there is a growing number of evidence of involvement of LRRK2 in different vesicle trafficking events, including endocytosis [152,171], Golgi clearance [43,51,126,150,151], cytoskeleton dynamics [40-43, 53, 115, 126, 138, 139, 150, 172-174], lysosomal dynamics [143], and autophagy [124,140,142,146,175]. Different pathogenic LRRK2 mutations can cause alterations of at least some of these events.…”

Section: Roc-cor Bidomain Mutationsmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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“…The push now is to understand the functions of these gene products and the biological pathways in which they operate. In PNAS, Beilina et al identify a number of LRRK2 interactors whose jobs are to process endocytosed vesicles, thereby associating LRRK2 with the vesicle endocytosis pathways (4).…”

mentioning

confidence: 99%

Pathway for Parkinson disease

Hoang

2014

Proc. Natl. Acad. Sci. U.S.A.

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

Cited by 334 publications

References 41 publications

Cellular processes associated with LRRK2 function and dysfunction

Cellular processes associated with LRRK2 function and dysfunction

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Pathway for Parkinson disease

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