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Behavioral Neurobiology of Huntington's Disease and Parkinson's Disease pp 331–368Cite as

Modeling LRRK2 Pathobiology in Parkinson’s Disease: From Yeast to Rodents

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Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 22))

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2, PARK8 ) gene represent the most common cause of familial Parkinson’s disease (PD) with autosomal dominant inheritance, whereas common variation at the LRRK2 genomic locus influences the risk of developing idiopathic PD. LRRK2 is a member of the ROCO protein family and contains multiple domains, including Ras-of-Complex (ROC) GTPase, kinase, and protein-protein interaction domains. In the last decade, the biochemical characterization of LRRK2 and the development of animal model s have provided important insight into the pathobiology of LRRK2. In this review, we comprehensively describe the different models employed to understand LRRK2-associated PD, including yeast, invertebrates, transgenic and viral-based rodents, and patient-derived induced pluripotent stem cells. We discuss how these models have contributed to understanding LRRK2 pathobiology and the advantages and limitations of each model for exploring aspects of LRRK2-associated PD.

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References

  • Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, Wade-Martins R (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 18:4022–4034

    PubMed Central  CAS  PubMed  Google Scholar 

  • Andres-Mateos E, Mejias R, Sasaki M, Li X, Lin BM, Biskup S, Zhang L, Banerjee R, Thomas B, Yang L, Liu G, Beal MF, Huso DL, Dawson TM, Dawson VL (2009) Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). J Neurosci 29:15846–15850

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bailey RM, Covy JP, Melrose HL, Rousseau L, Watkinson R, Knight J, Miles S, Farrer MJ, Dickson DW, Giasson BI, Lewis J (2013) LRRK2 phosphorylates novel tau epitopes and promotes tauopathy. Acta Neuropathol 126:809–827

    PubMed Central  CAS  PubMed  Google Scholar 

  • Baptista MA, Dave KD, Frasier MA, Sherer TB, Greeley M, Beck MJ, Varsho JS, Parker GA, Moore C, Churchill MJ, Meshul CK, Fiske BK (2013) Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs. PLoS ONE 8:e80705

    PubMed Central  PubMed  Google Scholar 

  • 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 JM, Greggio E, Cookson MR (2014) Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc Natl Acad Sci USA 111:2626–2631

    PubMed Central  CAS  PubMed  Google Scholar 

  • Berger Z, Smith KA, Lavoie MJ (2010) Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry 49:5511–5523

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bichler Z, Lim HC, Zeng L, Tan EK (2013) Non-motor and motor features in LRRK2 transgenic mice. PLoS ONE 8:e70249

    PubMed Central  CAS  PubMed  Google Scholar 

  • Biosa A, Trancikova A, Civiero L, Glauser L, Bubacco L, Greggio E, Moore DJ (2013) GTPase activity regulates kinase activity and cellular phenotypes of Parkinson’s disease-associated LRRK2. Hum Mol Genet 22:1140–1156

    CAS  PubMed  Google Scholar 

  • Biskup S, Moore DJ, Celsi F, Higashi S, West AB, Andrabi SA, Kurkinen K, Yu SW, Savitt JM, Waldvogel HJ, Faull RL, Emson PC, Torp R, Ottersen OP, Dawson TM, Dawson VL (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol 60:557–569

    CAS  PubMed  Google Scholar 

  • Biskup S, Moore DJ, Rea A, Lorenz-Deperieux B, Coombes CE, Dawson VL, Dawson TM, West AB (2007) Dynamic and redundant regulation of LRRK2 and LRRK1 expression. BMC Neurosci 8:102

    PubMed Central  PubMed  Google Scholar 

  • Biskup S, West AB (2009) Zeroing in on LRRK2-linked pathogenic mechanisms in Parkinson’s disease. Biochim Biophys Acta 7:625–633

    Google Scholar 

  • Bonifati V (2014) Genetics of Parkinson’s disease: state of the art, 2013. Parkinsonism Relat Disord 20(Suppl 1):S23–S28

    PubMed  Google Scholar 

  • Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259

    CAS  PubMed  Google Scholar 

  • Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118:401–415

    CAS  PubMed  Google Scholar 

  • Chartier-Harlin MC, Dachsel JC, Vilarino-Guell C, Lincoln SJ, Lepretre F, Hulihan MM, Kachergus J, Milnerwood AJ, Tapia L, Song MS, Le Rhun E, Mutez E, Larvor L, Duflot A, Vanbesien-Mailliot C, Kreisler A, Ross OA, Nishioka K, Soto-Ortolaza AI, Cobb SA, Melrose HL, Behrouz B, Keeling BH, Bacon JA, Hentati E, Williams L, Yanagiya A, Sonenberg N, Lockhart PJ, Zubair AC, Uitti RJ, Aasly JO, Krygowska-Wajs A, Opala G, Wszolek ZK, Frigerio R, Maraganore DM, Gosal D, Lynch T, Hutchinson M, Bentivoglio AR, Valente EM, Nichols WC, Pankratz N, Foroud T, Gibson RA, Hentati F, Dickson DW, Destee A, Farrer MJ (2011) Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet 89:398–406

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen CY, Weng YH, Chien KY, Lin KJ, Yeh TH, Cheng YP, Lu CS, Wang HL (2012) (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell Death Differ 19:1623–1633

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen L, Feany MB (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8:657–663

    CAS  PubMed  Google Scholar 

  • Choi HG, Zhang J, Deng X, Hatcher JM, Patricelli MP, Zhao Z, Alessi DR, Gray NS (2012) Brain penetrant LRRK2 inhibitor. ACS Med Chem Lett 3:658–662

    PubMed Central  CAS  PubMed  Google Scholar 

  • Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, Guo M (2006) Drosophila PINK1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166

    CAS  PubMed  Google Scholar 

  • Cookson MR (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson’s disease. Nat Rev Neurosci 11:791–797

    CAS  PubMed  Google Scholar 

  • Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S (2006) Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313:324–328

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cooper O, Seo H, Andrabi S, Guardia-Laguarta C, Graziotto J, Sundberg M, McLean JR, Carrillo-Reid L, Xie Z, Osborn T, Hargus G, Deleidi M, Lawson T, Bogetofte H, Perez-Torres E, Clark L, Moskowitz C, Mazzulli J, Chen L, Volpicelli-Daley L, Romero N, Jiang H, Uitti RJ, Huang Z, Opala G, Scarffe LA, Dawson VL, Klein C, Feng J, Ross OA, Trojanowski JQ, Lee VM, Marder K, Surmeier DJ, Wszolek ZK, Przedborski S, Krainc D, Dawson TM, Isacson O (2012) Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease. Sci Transl Med 4:3003985

    Google Scholar 

  • Crosiers D, Theuns J, Cras P, Van Broeckhoven C (2011) Parkinson disease: insights in clinical, genetic and pathological features of monogenic disease subtypes. J Chem Neuroanat 42:131–141

    CAS  PubMed  Google Scholar 

  • Daher JP, Pletnikova O, Biskup S, Musso A, Gellhaar S, Galter D, Troncoso JC, Lee MK, Dawson TM, Dawson VL, Moore DJ (2012) Neurodegenerative phenotypes in an A53T alpha-synuclein transgenic mouse model are independent of LRRK2. Hum Mol Genet 21:2420–2431

    PubMed Central  CAS  PubMed  Google Scholar 

  • Daniels V, Vancraenenbroeck R, Law BM, Greggio E, Lobbestael E, Gao F, De Maeyer M, Cookson MR, Harvey K, Baekelandt V, Taymans JM (2011) Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant. J Neurochem 116:304–315

    PubMed Central  CAS  PubMed  Google Scholar 

  • Di Fonzo A, Dekker MC, Montagna P, Baruzzi A, Yonova EH, Correia Guedes L, Szczerbinska A, Zhao T, Dubbel-Hulsman LO, Wouters CH, de Graaff E, Oyen WJ, Simons EJ, Breedveld GJ, Oostra BA, Horstink MW, Bonifati V (2009) FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology 72:240–245

    PubMed  Google Scholar 

  • Dodson MW, Zhang T, Jiang C, Chen S, Guo M (2012) Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning. Hum Mol Genet 21:1350–1363

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dranka BP, Gifford A, Ghosh A, Zielonka J, Joseph J, Kanthasamy AG, Kalyanaraman B (2013) Diapocynin prevents early Parkinson’s disease symptoms in the leucine-rich repeat kinase 2 (LRRK2R(1)(4)(4)(1)G) transgenic mouse. Neurosci Lett 549:57–62

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dusonchet J, Kochubey O, Stafa K, Young SM Jr, Zufferey R, Moore DJ, Schneider BL, Aebischer P (2011) A rat model of progressive nigral neurodegeneration induced by the Parkinson’s disease-associated G2019S mutation in LRRK2. J Neurosci 31:907–912

    CAS  PubMed  Google Scholar 

  • Edvardson S, Cinnamon Y, Ta-Shma A, Shaag A, Yim YI, Zenvirt S, Jalas C, Lesage S, Brice A, Taraboulos A, Kaestner KH, Greene LE, Elpeleg O (2012) A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLoS ONE 7:1

    Google Scholar 

  • Galter D, Westerlund M, Carmine A, Lindqvist E, Sydow O, Olson L (2006) LRRK2 expression linked to dopamine-innervated areas. Ann Neurol 59:714–719

    CAS  PubMed  Google Scholar 

  • Gasser T (2009) Mendelian forms of Parkinson’s disease. Biochim Biophys Acta 7:587–596

    Google Scholar 

  • Gehrke S, Imai Y, Sokol N, Lu B (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466:637–641

    PubMed Central  CAS  PubMed  Google Scholar 

  • Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ, Van Deerlin VM (2006) Biochemical and pathological characterization of LRRK2. Ann Neurol 59:315–322

    CAS  PubMed  Google Scholar 

  • Giesert F, Hofmann A, Burger A, Zerle J, Kloos K, Hafen U, Ernst L, Zhang J, Vogt-Weisenhorn DM, Wurst W (2013) Expression analysis of LRRK1, LRRK2 and LRRK2 splice variants in mice. PLoS One 8

    Google Scholar 

  • Gillardon F (2009) Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability—a point of convergence in parkinsonian neurodegeneration? J Neurochem 110:1514–1522

    CAS  PubMed  Google Scholar 

  • Gitler AD, Bevis BJ, Shorter J, Strathearn KE, Hamamichi S, Su LJ, Caldwell KA, Caldwell GA, Rochet JC, McCaffery JM, Barlowe C, Lindquist S (2008) The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci USA 105:145–150

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet JC, Lindquist S (2009) Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet 41:308–315

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O’Neill E, Meitinger T, Kolch W, Prokisch H, Ueffing M (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 15:223–232

    CAS  PubMed  Google Scholar 

  • Gloeckner CJ, Schumacher A, Boldt K, Ueffing M (2009) The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro. J Neurochem 109:959–968

    CAS  PubMed  Google Scholar 

  • Greggio E, Cookson MR (2009) Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: three questions. ASN Neuro 1

    Google Scholar 

  • Greggio E, Taymans JM, Zhen EY, Ryder J, Vancraenenbroeck R, Beilina A, Sun P, Deng J, Jaffe H, Baekelandt V, Merchant K, Cookson MR (2009) The Parkinson’s disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites. Biochem Biophys Res Commun 389:449–454

    PubMed Central  CAS  PubMed  Google Scholar 

  • Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans JM, Daniels V, Lewis P, Jain S, Ding J, Syed A, Thomas KJ, Baekelandt V, Cookson MR (2008) The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem 283:16906–16914

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hakimi M, Selvanantham T, Swinton E, Padmore RF, Tong Y, Kabbach G, Venderova K, Girardin SE, Bulman DE, Scherzer CR, LaVoie MJ, Gris D, Park DS, Angel JB, Shen J, Philpott DJ, Schlossmacher MG (2011) Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm 118:795–808

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hatano T, Kubo S, Imai S, Maeda M, Ishikawa K, Mizuno Y, Hattori N (2007) Leucine-rich repeat kinase 2 associates with lipid rafts. Hum Mol Genet 16:678–690

    CAS  PubMed  Google Scholar 

  • Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 7:583–590

    PubMed Central  CAS  PubMed  Google Scholar 

  • Herzig MC, Bidinosti M, Schweizer T, Hafner T, Stemmelen C, Weiss A, Danner S, Vidotto N, Stauffer D, Barske C, Mayer F, Schmid P, Rovelli G, van der Putten PH, Shimshek DR (2012) High LRRK2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain. PLoS ONE 7:15

    Google Scholar 

  • Herzig MC, Kolly C, Persohn E, Theil D, Schweizer T, Hafner T, Stemmelen C, Troxler TJ, Schmid P, Danner S, Schnell CR, Mueller M, Kinzel B, Grevot A, Bolognani F, Stirn M, Kuhn RR, Kaupmann K, van der Putten PH, Rovelli G, Shimshek DR (2011) LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum Mol Genet 20:4209–4223

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hindle S, Afsari F, Stark M, Middleton CA, Evans GJ, Sweeney ST, Elliott CJ (2013) Dopaminergic expression of the Parkinsonian gene LRRK2-G2019S leads to non-autonomous visual neurodegeneration, accelerated by increased neural demands for energy. Hum Mol Genet 22:2129–2140

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hinkle KM, Yue M, Behrouz B, Dachsel JC, Lincoln SJ, Bowles EE, Beevers JE, Dugger B, Winner B, Prots I, Kent CB, Nishioka K, Lin WL, Dickson DW, Janus CJ, Farrer MJ, Melrose HL (2012) LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors. Mol Neurodegener 7:25

    Google Scholar 

  • Hulihan MM, Ishihara-Paul L, Kachergus J, Warren L, Amouri R, Elango R, Prinjha RK, Upmanyu R, Kefi M, Zouari M, Sassi SB, Yahmed SB, El Euch-Fayeche G, Matthews PM, Middleton LT, Gibson RA, Hentati F, Farrer MJ (2008) LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study. Lancet Neurol 7:591–594

    CAS  PubMed  Google Scholar 

  • Imai Y, Gehrke S, Wang HQ, Takahashi R, Hasegawa K, Oota E, Lu B (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J 27:2432–2443

    PubMed Central  CAS  PubMed  Google Scholar 

  • International Parkinson Disease Genomics C, Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simon-Sanchez J, Schulte C, Lesage S, Sveinbjornsdottir S, Stefansson K, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW (2011) Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet 377:641–649

    Google Scholar 

  • Ito G, Okai T, Fujino G, Takeda K, Ichijo H, Katada T, Iwatsubo T (2007) GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson’s disease. Biochemistry 46:1380–1388

    CAS  PubMed  Google Scholar 

  • Jaleel M, Nichols RJ, Deak M, Campbell DG, Gillardon F, Knebel A, Alessi DR (2007) LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson’s disease mutants affect kinase activity. Biochem J 405:307–317

    PubMed Central  CAS  PubMed  Google Scholar 

  • James NG, Digman MA, Gratton E, Barylko B, Ding X, Albanesi JP, Goldberg MS, Jameson DM (2012) Number and brightness analysis of LRRK2 oligomerization in live cells. Biophys J 102:L41–L43

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376

    CAS  PubMed  Google Scholar 

  • Kamikawaji S, Ito G, Sano T, Iwatsubo T (2013) Differential effects of familial Parkinson mutations in LRRK2 Revealed by a systematic analysis of autophosphorylation. Biochemistry 23:23

    Google Scholar 

  • Kanao T, Venderova K, Park DS, Unterman T, Lu B, Imai Y (2010) Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila. Hum Mol Genet 19:3747–3758

    CAS  PubMed  Google Scholar 

  • Kawakami F, Yabata T, Ohta E, Maekawa T, Shimada N, Suzuki M, Maruyama H, Ichikawa T, Obata F (2012) LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth. PLoS ONE 7:27

    Google Scholar 

  • Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Bjorklund A (2002) Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22:2780–2791

    CAS  PubMed  Google Scholar 

  • Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608

    CAS  PubMed  Google Scholar 

  • Klein RL, King MA, Hamby ME, Meyer EM (2002) Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum Gene Ther 13:605–612

    CAS  PubMed  Google Scholar 

  • Krebs CE, Karkheiran S, Powell JC, Cao M, Makarov V, Darvish H, Di Paolo G, Walker RH, Shahidi GA, Buxbaum JD, De Camilli P, Yue Z, Paisan-Ruiz C (2013) The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Hum Mutat 34:1200–1207

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lang AE, Lozano AM (1998a) Parkinson’s disease. First of two parts. N Engl J Med 339:1044–1053

    CAS  PubMed  Google Scholar 

  • Lang AE, Lozano AM (1998b) Parkinson’s disease. Second of two parts. N Engl J Med 339:1130–1143

    CAS  PubMed  Google Scholar 

  • Lee BD, Shin JH, VanKampen J, Petrucelli L, West AB, Ko HS, Lee YI, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM (2010a) Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease. Nat Med 16:998–1000

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lee S, Liu HP, Lin WY, Guo H, Lu B (2010b) LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction. J Neurosci 30:16959–16969

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lee SB, Kim W, Lee S, Chung J (2007) Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochem Biophys Res Commun 358:534–539

    CAS  PubMed  Google Scholar 

  • Lewis PA, Greggio E, Beilina A, Jain S, Baker A, Cookson MR (2007) The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem Biophys Res Commun 357:668–671

    PubMed Central  CAS  PubMed  Google Scholar 

  • Li X, Patel JC, Wang J, Avshalumov MV, Nicholson C, Buxbaum JD, Elder GA, Rice ME, Yue Z (2010) Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson’s disease mutation G2019S. J Neurosci 30:1788–1797

    PubMed Central  CAS  PubMed  Google Scholar 

  • Li X, Tan YC, Poulose S, Olanow CW, Huang XY, Yue Z (2007) Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson’s disease R1441C/G mutants. J Neurochem 103:238–247

    PubMed Central  CAS  PubMed  Google Scholar 

  • Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, Bogdanov M, Przedborski S, Beal MF, Burke RE, Li C (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson’s disease. Nat Neurosci 12:826–828

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liao J, Wu CX, Burlak C, Zhang S, Sahm H, Wang M, Zhang ZY, Vogel KW, Federici M, Riddle SM, Nichols RJ, Liu D, Cookson MR, Stone TA, Hoang QQ (2014) Parkinson disease-associated mutation R1441H in LRRK2 prolongs the “active state” of its GTPase domain. Proc Natl Acad Sci USA 3:3

    Google Scholar 

  • Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide BM, Schjeide LM, Meissner E, Zauft U, Allen NC, Liu T, Schilling M, Anderson KJ, Beecham G, Berg D, Biernacka JM, Brice A, DeStefano AL, Do CB, Eriksson N, Factor SA, Farrer MJ, Foroud T, Gasser T, Hamza T, Hardy JA, Heutink P, Hill-Burns EM, Klein C, Latourelle JC, Maraganore DM, Martin ER, Martinez M, Myers RH, Nalls MA, Pankratz N, Payami H, Satake W, Scott WK, Sharma M, Singleton AB, Stefansson K, Toda T, Tung JY, Vance J, Wood NW, Zabetian CP, Young P, Tanzi RE, Khoury MJ, Zipp F, Lehrach H, Ioannidis JP, Bertram L (2012) Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: the PDGene database. PLoS Genet 8:15

    Google Scholar 

  • Lin CH, Tsai PI, Wu RM, Chien CT (2010) LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3ss. J Neurosci 30:13138–13149

    CAS  PubMed  Google Scholar 

  • Lin X, Parisiadou L, Gu XL, Wang L, Shim H, Sun L, Xie C, Long CX, Yang WJ, Ding J, Chen ZZ, Gallant PE, Tao-Cheng JH, Rudow G, Troncoso JC, Liu Z, Li Z, Cai H (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant alpha-synuclein. Neuron 64:807–827

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liu HF, Lu S, Ho PWL, Tse HM, Pang SYY, Kung MHW, Ho JWM, Ramsden DB, Zhou ZJ, Ho SL (2014) LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity. Ann Clin Trans Neurol 1:199–208

    CAS  Google Scholar 

  • Liu GH, Qu J, Suzuki K, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W, Wagner U, Kim A, Ren B, Li Y, Goebl A, Kim J, Soligalla RD, Dubova I, Thompson J, Yates J 3rd, Esteban CR, Sancho-Martinez I, Izpisua Belmonte JC (2012) Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491:603–607

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liu Z, Hamamichi S, Lee BD, Yang D, Ray A, Caldwell GA, Caldwell KA, Dawson TM, Smith WW, Dawson VL (2011) Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson’s disease models. Hum Mol Genet 20:3933–3942

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liu Z, Wang X, Yu Y, Li X, Wang T, Jiang H, Ren Q, Jiao Y, Sawa A, Moran T, Ross CA, Montell C, Smith WW (2008) A Drosophila model for LRRK2-linked Parkinsonism. Proc Natl Acad Sci USA 105:2693–2698

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lo Bianco C, Ridet JL, Schneider BL, Deglon N, Aebischer P (2002) Alpha-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc Natl Acad Sci USA 99:10813–10818

    PubMed Central  CAS  PubMed  Google Scholar 

  • Low K, Aebischer P (2012) Use of viral vectors to create animal models for Parkinson’s disease. Neurobiol Dis 48:189–201

    PubMed  Google Scholar 

  • MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52:587–593

    CAS  PubMed  Google Scholar 

  • MacLeod DA, Rhinn H, Kuwahara T, Zolin A, Di Paolo G, McCabe BD, Marder KS, Honig LS, Clark LN, Small SA, Abeliovich A (2013) RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron 77:425–439

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mandemakers W, Snellinx A, O’Neill MJ, de Strooper B (2012) LRRK2 expression is enriched in the striosomal compartment of mouse striatum. Neurobiol Dis 48:582–593

    CAS  PubMed  Google Scholar 

  • Marin I (2008) Ancient origin of the Parkinson disease gene LRRK2. J Mol Evol 67:41–50

    CAS  PubMed  Google Scholar 

  • Matta S, Van Kolen K, da Cunha R, van den Bogaart G, Mandemakers W, Miskiewicz K, De Bock PJ, Morais VA, Vilain S, Haddad D, Delbroek L, Swerts J, Chavez-Gutierrez L, Esposito G, Daneels G, Karran E, Holt M, Gevaert K, Moechars DW, De Strooper B, Verstreken P (2012) LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 75:1008–1021

    CAS  PubMed  Google Scholar 

  • Melrose HL, Dachsel JC, Behrouz B, Lincoln SJ, Yue M, Hinkle KM, Kent CB, Korvatska E, Taylor JP, Witten L, Liang YQ, Beevers JE, Boules M, Dugger BN, Serna VA, Gaukhman A, Yu X, Castanedes-Casey M, Braithwaite AT, Ogholikhan S, Yu N, Bass D, Tyndall G, Schellenberg GD, Dickson DW, Janus C, Farrer MJ (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol Dis 40:503–517

    PubMed Central  CAS  PubMed  Google Scholar 

  • Meulener M, Whitworth AJ, Armstrong-Gold CE, Rizzu P, Heutink P, Wes PD, Pallanck LJ, Bonini NM (2005) Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson’s disease. Curr Biol 15:1572–1577

    CAS  PubMed  Google Scholar 

  • Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG, DeSilva TM, Cowell RM, West AB (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 32:1602–1611 The Official Journal of the Society for Neuroscience

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ness D, Ren Z, Gardai S, Sharpnack D, Johnson VJ, Brennan RJ, Brigham EF, Olaharski AJ (2013) Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. PLoS One 8

    Google Scholar 

  • Ng CH, Guan MS, Koh C, Ouyang X, Yu F, Tan EK, O’Neill SP, Zhang X, Chung J, Lim KL (2012) AMP kinase activation mitigates dopaminergic dysfunction and mitochondrial abnormalities in Drosophila models of Parkinson’s disease. J Neurosci 32:14311–14317

    CAS  PubMed  Google Scholar 

  • Ng CH, Mok SZ, Koh C, Ouyang X, Fivaz ML, Tan EK, Dawson VL, Dawson TM, Yu F, Lim KL (2009) Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. J Neurosci 29:11257–11262

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nguyen HN, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P, Kee K, Schule B, Dolmetsch RE, Langston W, Palmer TD, Pera RR (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8:267–280

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ohta E, Kawakami F, Kubo M, Obata F (2011) LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: impairment of the kinase activity by Parkinson’s disease-associated mutations. FEBS Lett 585:2165–2170

    CAS  PubMed  Google Scholar 

  • Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig LS, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo AM (2013) Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 16:394–406

    PubMed Central  CAS  PubMed  Google Scholar 

  • Outeiro TF, Lindquist S (2003) Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science 302:1772–1775

    PubMed Central  CAS  PubMed  Google Scholar 

  • Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J, Wood NW, Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600

    CAS  PubMed  Google Scholar 

  • Parisiadou L, Xie C, Cho HJ, Lin X, Gu XL, Long CX, Lobbestael E, Baekelandt V, Taymans JM, Sun L, Cai H (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J Neurosci 29:13971–13980

    PubMed Central  CAS  PubMed  Google Scholar 

  • Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ (2008) Disease-specific induced pluripotent stem cells. Cell 134:877–886

    PubMed Central  CAS  PubMed  Google Scholar 

  • Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, Chung J (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161

    CAS  PubMed  Google Scholar 

  • Paus M, Kohl Z, Ben Abdallah NM, Galter D, Gillardon F, Winkler J (2013) Enhanced dendritogenesis and axogenesis in hippocampal neuroblasts of LRRK2 knockout mice. Brain Res 25:85–100

    Google Scholar 

  • Pereira C, Miguel Martins L, Saraiva L (2014) LRRK2, but not pathogenic mutants, protects against HO stress depending on mitochondrial function and endocytosis in a yeast model. Biochim Biophys Acta 24:00072–00076

    Google Scholar 

  • Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    CAS  PubMed  Google Scholar 

  • Qing H, Wong W, McGeer EG, McGeer PL (2009) LRRK2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications. Biochem Biophys Res Commun 387:149–152

    CAS  PubMed  Google Scholar 

  • Quadri M, Fang M, Picillo M, Olgiati S, Breedveld GJ, Graafland J, Wu B, Xu F, Erro R, Amboni M, Pappata S, Quarantelli M, Annesi G, Quattrone A, Chien HF, Barbosa ER, Oostra BA, Barone P, Wang J, Bonifati V (2013) Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum Mutat 34:1208–1215

    CAS  PubMed  Google Scholar 

  • Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J, Al-Din A, Hillmer AM, Karsak M, Liss B, Woods CG, Behrens MI, Kubisch C (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38:1184–1191

    CAS  PubMed  Google Scholar 

  • Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ (2011) Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS ONE 6:0018568

    Google Scholar 

  • Reinhardt P, Schmid B, Burbulla LF, Schondorf DC, Wagner L, Glatza M, Hoing S, Hargus G, Heck SA, Dhingra A, Wu G, Muller S, Brockmann K, Kluba T, Maisel M, Kruger R, Berg D, Tsytsyura Y, Thiel CS, Psathaki OE, Klingauf J, Kuhlmann T, Klewin M, Muller H, Gasser T, Scholer HR, Sterneckert J (2013) Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12:354–367

    CAS  PubMed  Google Scholar 

  • Reith AD, Bamborough P, Jandu K, Andreotti D, Mensah L, Dossang P, Choi HG, Deng X, Zhang J, Alessi DR, Gray NS (2012) GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg Med Chem Lett 22:5625–5629

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ren G, Xin S, Li S, Zhong H, Lin S (2011) Disruption of LRRK2 does not cause specific loss of dopaminergic neurons in zebrafish. PLoS ONE 6:16

    Google Scholar 

  • Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, Litvan I, Gordon MF, Wszolek ZK, Farrer MJ, Dickson DW (2006) LRRK2 and Lewy body disease. Ann Neurol 59:388–393

    CAS  PubMed  Google Scholar 

  • Saha S, Guillily MD, Ferree A, Lanceta J, Chan D, Ghosh J, Hsu CH, Segal L, Raghavan K, Matsumoto K, Hisamoto N, Kuwahara T, Iwatsubo T, Moore L, Goldstein L, Cookson M, Wolozin B (2009) LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci 29:9210–9218

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sakaguchi-Nakashima A, Meir JY, Jin Y, Matsumoto K, Hisamoto N (2007) LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Curr Biol 17:592–598

    CAS  PubMed  Google Scholar 

  • Samann J, Hegermann J, von Gromoff E, Eimer S, Baumeister R, Schmidt E (2009) Caenorhabditits elegans LRK-1 and PINK1 act antagonistically in stress response and neurite outgrowth. J Biol Chem 284:16482–16491

    PubMed Central  PubMed  Google Scholar 

  • Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimenez-Delgado S, Caig C, Mora S, Di Guglielmo C, Ezquerra M, Patel B, Giralt A, Canals JM, Memo M, Alberch J, Lopez-Barneo J, Vila M, Cuervo AM, Tolosa E, Consiglio A, Raya A (2012) Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson’s disease. EMBO Mol Med 4:380–395

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sanders LH, Laganiere J, Cooper O, Mak SK, Vu BJ, Huang YA, Paschon DE, Vangipuram M, Sundararajan R, Urnov FD, Langston JW, Gregory PD, Zhang HS, Greenamyre JT, Isacson O, Schule B (2014) LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson’s disease patients: reversal by gene correction. Neurobiol Dis 62:381–386

    CAS  PubMed  Google Scholar 

  • Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet 41:1303–1307

    CAS  PubMed  Google Scholar 

  • Sen S, Webber PJ, West AB (2009) Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. J Biol Chem 284:36346–36356

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sheng D, Qu D, Kwok KH, Ng SS, Lim AY, Aw SS, Lee CW, Sung WK, Tan EK, Lufkin T, Jesuthasan S, Sinnakaruppan M, Liu J (2010) Deletion of the WD40 domain of LRRK2 in Zebrafish causes Parkinsonism-like loss of neurons and locomotive defect. PLoS Genet 6:1000914

    Google Scholar 

  • Sheng Z, Zhang S, Bustos D, Kleinheinz T, Le Pichon CE, Dominguez SL, Solanoy HO, Drummond J, Zhang X, Ding X, Cai F, Song Q, Li X, Yue Z, van der Brug MP, Burdick DJ, Gunzner-Toste J, Chen H, Liu X, Estrada AA, Sweeney ZK, Scearce-Levie K, Moffat JG, Kirkpatrick DS, Zhu H (2012) Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci Transl Med 4:3004485

    Google Scholar 

  • Shiba Y, Randazzo PA (2012) ArfGAP1 function in COPI mediated membrane traffic: currently debated models and comparison to other coat-binding ArfGAPs. Histol Histopathol 27:1143–1153

    CAS  PubMed  Google Scholar 

  • Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Kruger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41:1308–1312

    PubMed Central  CAS  PubMed  Google Scholar 

  • Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) Alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841

    CAS  PubMed  Google Scholar 

  • Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R (2009) Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136:964–977

    PubMed Central  CAS  PubMed  Google Scholar 

  • Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    CAS  PubMed  Google Scholar 

  • Stafa K, Trancikova A, Webber PJ, Glauser L, West AB, Moore DJ (2012) GTPase activity and neuronal toxicity of Parkinson’s disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet 8:9

    Google Scholar 

  • Su YC, Qi X (2013) Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet 27:27

    Google Scholar 

  • Tain LS, Mortiboys H, Tao RN, Ziviani E, Bandmann O, Whitworth AJ (2009) Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat Neurosci 12:1129–1135

    PubMed Central  CAS  PubMed  Google Scholar 

  • Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    CAS  PubMed  Google Scholar 

  • Taymans JM, Vancraenenbroeck R, Ollikainen P, Beilina A, Lobbestael E, De Maeyer M, Baekelandt V, Cookson MR (2011) LRRK2 kinase activity is dependent on LRRK2 GTP binding capacity but independent of LRRK2 GTP binding. PLoS ONE 6:e23207

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tong Y, Pisani A, Martella G, Karouani M, Yamaguchi H, Pothos EN, Shen J (2009) R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proc Natl Acad Sci USA 106:14622–14627

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tong Y, Yamaguchi H, Giaime E, Boyle S, Kopan R, Kelleher RJ 3rd, Shen J (2010) Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proc Natl Acad Sci USA 107:9879–9884

    PubMed Central  CAS  PubMed  Google Scholar 

  • Trancikova A, Mamais A, Webber PJ, Stafa K, Tsika E, Glauser L, West AB, Bandopadhyay R, Moore DJ (2012) Phosphorylation of 4E-BP1 in the mammalian brain is not altered by LRRK2 expression or pathogenic mutations. PLoS ONE 7:e47784

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tsika E, Moore DJ (2012) Mechanisms of LRRK2-mediated neurodegeneration. Curr Neurol Neurosci Rep 12:251–260

    CAS  PubMed  Google Scholar 

  • Tsika E, Moore DJ (2013) Contribution of GTPase activity to LRRK2-associated Parkinson disease. Small GTPases 4

    Google Scholar 

  • Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160

    CAS  PubMed  Google Scholar 

  • Venderova K, Kabbach G, Abdel-Messih E, Zhang Y, Parks RJ, Imai Y, Gehrke S, Ngsee J, Lavoie MJ, Slack RS, Rao Y, Zhang Z, Lu B, Haque ME, Park DS (2009) Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK1 in a Drosophila melanogaster model of Parkinson’s disease. Hum Mol Genet 18:4390–4404

    CAS  PubMed  Google Scholar 

  • Vilarino-Guell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI, Cobb SA, Wilhoite GJ, Bacon JA, Behrouz B, Melrose HL, Hentati E, Puschmann A, Evans DM, Conibear E, Wasserman WW, Aasly JO, Burkhard PR, Djaldetti R, Ghika J, Hentati F, Krygowska-Wajs A, Lynch T, Melamed E, Rajput A, Rajput AH, Solida A, Wu RM, Uitti RJ, Wszolek ZK, Vingerhoets F, Farrer MJ (2011) VPS35 mutations in Parkinson disease. Am J Hum Genet 89:162–167

    PubMed Central  PubMed  Google Scholar 

  • Wang D, Tang B, Zhao G, Pan Q, Xia K, Bodmer R, Zhang Z (2008a) Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons. Mol Neurodegener 3:3

    Google Scholar 

  • Wang L, Xie C, Greggio E, Parisiadou L, Shim H, Sun L, Chandran J, Lin X, Lai C, Yang WJ, Moore DJ, Dawson TM, Dawson VL, Chiosis G, Cookson MR, Cai H (2008b) The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2. J Neurosci 28:3384–3391

    PubMed Central  CAS  PubMed  Google Scholar 

  • Webber PJ, Smith AD, Sen S, Renfrow MB, Mobley JA, West AB (2011) Autophosphorylation in the leucine-rich repeat kinase 2 (LRRK2) GTPase domain modifies kinase and GTP-binding activities. J Mol Biol 412:94–110

    PubMed Central  CAS  PubMed  Google Scholar 

  • West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM (2005) Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 102:16842–16847

    PubMed Central  CAS  PubMed  Google Scholar 

  • West AB, Moore DJ, Choi C, Andrabi SA, Li X, Dikeman D, Biskup S, Zhang Z, Lim KL, Dawson VL, Dawson TM (2007) Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 16:223–232

    CAS  PubMed  Google Scholar 

  • Westerlund M, Belin AC, Anvret A, Bickford P, Olson L, Galter D (2008) Developmental regulation of leucine-rich repeat kinase 1 and 2 expression in the brain and other rodent and human organs: implications for Parkinson’s disease. Neuroscience 152:429–436

    CAS  PubMed  Google Scholar 

  • Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ (2003) Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein. Science 302:1769–1772

    CAS  PubMed  Google Scholar 

  • Winner B, Melrose HL, Zhao C, Hinkle KM, Yue M, Kent C, Braithwaite AT, Ogholikhan S, Aigner R, Winkler J, Farrer MJ, Gage FH (2011) Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol Dis 41:706–716

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wolozin B, Saha S, Guillily M, Ferree A, Riley M (2008) Investigating convergent actions of genes linked to familial Parkinson’s disease. Neurodegener Dis 5:182–185

    PubMed Central  CAS  PubMed  Google Scholar 

  • Xiong Y, Coombes CE, Kilaru A, Li X, Gitler AD, Bowers WJ, Dawson VL, Dawson TM, Moore DJ (2010) GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genet 6:1000902

    Google Scholar 

  • Xiong Y, Yuan C, Chen R, Dawson TM, Dawson VL (2012) ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2. J Neurosci 32:3877–3886

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yao C, El Khoury R, Wang W, Byrd TA, Pehek EA, Thacker C, Zhu X, Smith MA, Wilson-Delfosse AL, Chen SG (2010) LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson’s disease. Neurobiol Dis 40:73–81

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yao C, Johnson WM, Gao Y, Wang W, Zhang J, Deak M, Alessi DR, Zhu X, Mieyal JJ, Roder H, Wilson-Delfosse AL, Chen SG (2013) Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity. Hum Mol Genet 22:328–344

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yeger-Lotem E, Riva L, Su LJ, Gitler AD, Cashikar AG, King OD, Auluck PK, Geddie ML, Valastyan JS, Karger DR, Lindquist S, Fraenkel E (2009) Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity. Nat Genet 41:316–323

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920

    CAS  PubMed  Google Scholar 

  • Yuan Y, Cao P, Smith MA, Kramp K, Huang Y, Hisamoto N, Matsumoto K, Hatzoglou M, Jin H, Feng Z (2011) Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C. elegans. PLoS ONE 6:3

    Google Scholar 

  • Yun HJ, Park J, Ho DH, Kim H, Kim CH, Oh H, Ga I, Seo H, Chang S, Son I, Seol W (2013) LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25. Exp Mol Med 16:68

    Google Scholar 

  • Zhou H, Huang C, Tong J, Hong WC, Liu YJ, Xia XG (2011) Temporal expression of mutant LRRK2 in adult rats impairs dopamine reuptake. Int J Biol Sci 7:753–761

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zimprich A, Benet-Pages A, Struhal W, Graf E, Eck SH, Offman MN, Haubenberger D, Spielberger S, Schulte EC, Lichtner P, Rossle SC, Klopp N, Wolf E, Seppi K, Pirker W, Presslauer S, Mollenhauer B, Katzenschlager R, Foki T, Hotzy C, Reinthaler E, Harutyunyan A, Kralovics R, Peters A, Zimprich F, Brucke T, Poewe W, Auff E, Trenkwalder C, Rost B, Ransmayr G, Winkelmann J, Meitinger T, Strom TM (2011) A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson’s disease. Am J Hum Genet 89:168–175

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful for funding support from the Swiss National Science Foundation (grant no. 31003A_144063), Michael J. Fox Foundation for Parkinson’s Research, National Institutes of Health (R01 NS076160) and the EPFL.

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Authors and Affiliations

  1. School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland

    Guillaume Daniel & Darren J. Moore

  2. Center for Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI, 49503, USA

    Darren J. Moore

Authors
  1. Guillaume Daniel
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  2. Darren J. Moore
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Correspondence to Darren J. Moore .

Editor information

Editors and Affiliations

  1. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany

    Hoa Huu Phuc Nguyen

  2. Dept of Experimental Medical Science, Lund University, Lund, Sweden

    M. Angela Cenci

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© 2014 Springer-Verlag Berlin Heidelberg

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Daniel, G., Moore, D.J. (2014). Modeling LRRK2 Pathobiology in Parkinson’s Disease: From Yeast to Rodents. In: Nguyen, H., Cenci, M. (eds) Behavioral Neurobiology of Huntington's Disease and Parkinson's Disease. Current Topics in Behavioral Neurosciences, vol 22. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2014_311

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