, Volume 11, Issue 4, pp 738–750 | Cite as

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

  • Iakov N. Rudenko
  • Mark R. CooksonEmail author


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.

Key Words:

Parkinson’s disease kinase inhibitors GTPase vesicular trafficking cytoskeleton treatment. 



We thank Dr. Aleksandra Beilina for fruitful discussions.


This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

Competing Interests

The authors have no competing interests.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2014_284_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1224 kb)


  1. 1.
    Lees AJ, Hardy J, Revesz T. Parkinson's disease. Lancet 2009;373:2055-2066.PubMedGoogle Scholar
  2. 2.
    Halliday G, Lees A, Stern M. Milestones in Parkinson's disease—clinical and pathologic features. Mov Disord 2011;26:1015-1021.PubMedGoogle Scholar
  3. 3.
    Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson's disease: progress and therapeutic implications. Mov Disord 2013;28:14-23.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Simón-Sánchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009;41:1308-1312.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Satake W, Nakabayashi Y, Mizuta I, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 2009;41:1303-1307.PubMedGoogle Scholar
  6. 6.
    Haugarvoll K, Wszolek ZK. Clinical features of LRRK2 parkinsonism. Parkinsonism Relat Disord.2009;15(Suppl. 3):S205-S208.PubMedGoogle Scholar
  7. 7.
    Healy DG, Falchi M, O'Sullivan SS, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 2008;7:583-590.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Cookson MR, Hardy J, Lewis PA. Genetic neuropathology of Parkinson’s disease. Int J Clin Exp Pathol 2008;1:217-231.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004;44:595-600.PubMedGoogle Scholar
  10. 10.
    Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601-607.PubMedGoogle Scholar
  11. 11.
    Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 2002;51:296-301.PubMedGoogle Scholar
  12. 12.
    West AB, Moore DJ, Biskup S, et al. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 2005;102:16842-16847.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Greggio E, Jain S, Kingsbury A, et al. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 2006;23:329-341.PubMedGoogle Scholar
  14. 14.
    Gloeckner CJ, Kinkl N, Schumacher A, et al. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 2006;15:223-232.PubMedGoogle Scholar
  15. 15.
    Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 2006;9:1231-1233.PubMedGoogle Scholar
  16. 16.
    Lesage S, Leutenegger AL, Brice A. LRRK2: a gene belonging to the ROCO family is implicated in the Parkinson's disease. Med Sci (Paris) 2005;21:1015-1017.Google Scholar
  17. 17.
    Marin I. The Parkinson disease gene LRRK2: evolutionary and structural insights. Mol Biol Evol 2006;23:2423-2433.PubMedGoogle Scholar
  18. 18.
    Lewis PA, Greggio E, Beilina A, Jain S, Baker A, Cookson MR. The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem Biophys Res Commun 2007;357:668-671.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Li X, Tan YC, Poulose S, Olanow CW, Huang XY, Yue Z. Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. J Neurochem 2007;103:238-247.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Guo L, Gandhi PN, Wang W, Petersen RB, Wilson-Delfosse AL, Chen SG. The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Exp Cell Res 2007;313:3658-3670.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Taymans JM, Vancraenenbroeck R, Ollikainen P, et al. LRRK2 kinase activity is dependent on LRRK2 GTP binding capacity but independent of LRRK2 GTP binding. PLoS One 2011;6:e23207.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Liu M, Dobson B, Glicksman MA, Yue Z, Stein RL. Kinetic mechanistic studies of wild-type leucine-rich repeat kinase 2: characterization of the kinase and GTPase activities. Biochemistry 2010;49:2008-2017.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Ito G, Okai T, Fujino G, et al. GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. Biochemistry 2007;46:1380-1388.PubMedGoogle Scholar
  24. 24.
    Greggio E, Zambrano I, Kaganovich A, et al. The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem.2008;283:16906-16914.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Greggio E, Taymans JM, Zhen EY, et al. The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites. Biochem Biophys Res Commun 2009;389:449-454.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Kamikawaji S, Ito G, Iwatsubo T. Identification of the autophosphorylation sites of LRRK2. Biochemistry 2009;48:10963-10975.PubMedGoogle Scholar
  27. 27.
    Li X, Moore DJ, Xiong Y, Dawson TM, Dawson VL. Reevaluation of phosphorylation sites in the Parkinson disease-associated leucine-rich repeat kinase 2. J Biol Chem 2010;285:29569-29576.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Gloeckner CJ, Boldt K, von Zweydorf F, et al. Phosphopeptide analysis reveals two discrete clusters of phosphorylation in the N-terminus and the Roc domain of the Parkinson-disease associated protein kinase LRRK2. J Proteome Res 2010;9:1738-1745.PubMedGoogle Scholar
  29. 29.
    Webber PJ, Smith AD, Sen S, Renfrow MB, Mobley JA, West AB. Autophosphorylation in the leucine-rich repeat kinase 2 (LRRK2) GTPase domain modifies kinase and GTP-binding activities. J Mol Biol 2011;412:94-110.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Taymans JM. The GTPase function of LRRK2. Biochem Soc Trans 2012;40:1063-1069.PubMedGoogle Scholar
  31. 31.
    Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA. LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci 2006;29:286-293.PubMedGoogle Scholar
  32. 32.
    Haebig K, Gloeckner CJ, Miralles MG, et al. ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2. PLoS One 2010;5:e13762.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Stafa K, Trancikova A, Webber PJ, Glauser L, West AB, Moore DJ. GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet 2012;8:e1002526.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Xiong Y, Yuan C, Chen R, Dawson TM, Dawson VL. ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2. J Neurosci 2012;32:3877-3886.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Tsika E, Moore DJ. Mechanisms of LRRK2-mediated neurodegeneration. Curr Neurol Neurosci Rep 2012;12:251-260.PubMedGoogle Scholar
  36. 36.
    Gasper R, Meyer S, Gotthardt K, Sirajuddin M, Wittinghofer A. It takes two to tango - regulation of G proteins by dimerization. Nat Rev Mol Cell Biol 2009;10:423-429.PubMedGoogle Scholar
  37. 37.
    Berger Z, Smith KA, Lavoie MJ. Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry 2010;49:5511-5523.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Sen S, Webber PJ, West AB. Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. J Biol Chem 2009;284:36346-36356.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Civiero L, Vancraenenbroeck R, Belluzzi E, et al. Biochemical characterization of highly purified leucine-rich repeat kinases 1 and 2 demonstrates formation of homodimers. PLoS One 2012;7:e43472.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Gandhi PN, Wang X, Zhu X, Chen SG, Wilson-Delfosse AL. The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules. J Neurosci Res 2008;86:1711-1720.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Kett LR, Boassa D, Ho CC, et al. LRRK2 Parkinson disease mutations enhance its microtubule association. Hum Mol Genet 2012;21:890-899.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Caesar M, Zach S, Carlson CB, Brockmann K, Gasser T, Gillardon F. Leucine-rich repeat kinase 2 functionally interacts with microtubules and kinase-dependently modulates cell migration. Neurobiol Dis 2013;54:280-288.PubMedGoogle Scholar
  43. 43.
    Gillardon F. Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability--a point of convergence in parkinsonian neurodegeneration? J Neurochem 2009;110:1514-1522.Google Scholar
  44. 44.
    Nichols RJ, Dzamko N, Morrice NA, et al. 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochem J 2010;430:393-404.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Dzamko N, Deak M, Hentati F, et al. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem J 2010;430:405-413.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Hsu CH, Chan D, Greggio E, et al. MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2. J Neurochem 2010;112:1593-1604.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Sancho RM, Law BM, Harvey K. Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways. Hum Mol Genet 2009;18:3955-3968.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Cookson MR. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci 2010;11:791-797.PubMedGoogle Scholar
  49. 49.
    Tong Y, Yamaguchi H, Giaime E, et al. 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 U S A 2010;107:9879-9884.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Herzig MC, Kolly C, Persohn E, et al. LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum Mol Genet 2011;20:4209-4223.PubMedPubMedCentralGoogle Scholar
  51. 51.
    MacLeod DA, Rhinn H, Kuwahara T, et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 2013;77:425-439.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Piccoli G, Condliffe SB, Bauer M, et al. LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool. J Neurosci 2011;31:2225-2237.PubMedGoogle Scholar
  53. 53.
    Melrose HL, Dachsel JC, Behrouz B, et al. Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol Dis 2010;40:503-517.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Li X, Patel JC, Wang J, et al. Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson's disease mutation G2019S. J Neurosci 2010;30:1788-1797.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Parisiadou L, Yu J, Sgobio C, et al. LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity. Nat Neurosci 2014;17:367-376.PubMedPubMedCentralGoogle Scholar
  56. 56.
    MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A. The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 2006;52:587-593.PubMedGoogle Scholar
  57. 57.
    Parisiadou L, Xie C, Cho HJ, et al. Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J Neurosci 2009;29:13971-13980.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Aasly JO, Vilarino-Guell C, Dachsel JC, et al. Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease. Mov Disord 2010;25:2156-2163.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Gasser T. Molecular pathogenesis of Parkinson disease: insights from genetic studies. Expert Rev Mol Med 2009;11:e22.PubMedGoogle Scholar
  60. 60.
    Goldwurm S, Di Fonzo A, Simons EJ, et al. The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor. J Med Genet 2005;42:e65.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Gilks WP, Abou-Sleiman PM, Gandhi S, et al. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 2005;365:415-416.PubMedGoogle Scholar
  62. 62.
    Infante J, Rodriguez E, Combarros O, et al. LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease. Neurosci Lett 2006;395:224-226.PubMedGoogle Scholar
  63. 63.
    Bras JM, Guerreiro RJ, Ribeiro MH, et al. G2019S dardarin substitution is a common cause of Parkinson's disease in a Portuguese cohort. Mov Disord 2005;20:1653-1655.PubMedGoogle Scholar
  64. 64.
    Ozelius LJ, Senthil G, Saunders-Pullman R, et al. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med 2006;354:424-425.PubMedGoogle Scholar
  65. 65.
    Lesage S, Dürr A, Tazir M, et al. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med 2006;354:422-423.PubMedGoogle Scholar
  66. 66.
    Liu M, Bender SA, Cuny GD, Sherman W, Glicksman M, Ray SS. Type II Kinase inhibitors show an unexpected inhibition mode against Parkinson's disease-linked LRRK2 mutant G2019S. Biochemistry 2013;12:1725-1736.Google Scholar
  67. 67.
    Jaleel M, Nichols RJ, Deak M, et al. LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem J 2007;405:307-317.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Anand VS, Reichling LJ, Lipinski K, et al. Investigation of leucine-rich repeat kinase 2 : enzymological properties and novel assays. FEBS J 2009;276:466-478.Google Scholar
  69. 69.
    Luzon-Toro B, Rubio de la Torre E, Delgado A, Perez-Tur J, Hilfiker S. Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation. Hum Mol Genet 2007;16:2031-2039.PubMedGoogle Scholar
  70. 70.
    Iaccarino C, Crosio C, Vitale C, Sanna G, Carri MT, Barone P. Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum Mol Genet 2007;16:1319-1326.PubMedGoogle Scholar
  71. 71.
    Covy JP, Giasson BI. Identification of compounds that inhibit the kinase activity of leucine-rich repeat kinase 2. Biochem Biophys Res Commun 2009;378:473-477.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Kumar A, Greggio E, Beilina A, et al. The Parkinson's disease associated LRRK2 exhibits weaker in vitro phosphorylation of 4E-BP compared to autophosphorylation. PLoS One 2010;5:e8730.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Rudenko IN, Kaganovich A, Hauser DN, et al. The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation. Biochem J 2012;446:99-111.PubMedGoogle Scholar
  74. 74.
    Funayama M, Hasegawa K, Ohta E, et al. An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol 2005;57:918-921.PubMedGoogle Scholar
  75. 75.
    Imai Y, Gehrke S, Wang HQ, et al. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J 2008;17:2432-2443Google Scholar
  76. 76.
    Kamikawaji S, Ito G, Sano T, Iwatsubo T. Differential effects of familial Parkinson mutations in LRRK2 revealed by a systematic analysis of autophosphorylation. Biochemistry 2013;52:6052-6062.PubMedGoogle Scholar
  77. 77.
    Ray S, Bender S, Kang S, Lin R, Glicksman MA, Liu M. The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity. J Biol Chem 2014;289:13042-13053.PubMedGoogle Scholar
  78. 78.
    Greggio E, Cookson MR. Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro 2009;1.Google Scholar
  79. 79.
    Haugarvoll K, Rademakers R, Kachergus JM, et al. Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease. Neurology 2008;70:1456-1460.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Simon-Sanchez J, Marti-Masso JF, Sanchez-Mut JV, et al. Parkinson's disease due to the R1441G mutation in Dardarin: a founder effect in the Basques. Mov Disord 2006;21:1954-1959.PubMedGoogle Scholar
  81. 81.
    Mata IF, Kachergus JM, Taylor JP, et al. Lrrk2 pathogenic substitutions in Parkinson's disease. Neurogenetics 2005;6:171-177.PubMedGoogle Scholar
  82. 82.
    Zabetian CP, Samii A, Mosley AD, et al. A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations. Neurology 2005;65:741-744.PubMedGoogle Scholar
  83. 83.
    Spanaki C, Latsoudis H, Plaitakis A. LRRK2 mutations on Crete: R1441H associated with PD evolving to PSP. Neurology 2006;67:1518-1519.PubMedGoogle Scholar
  84. 84.
    Ross OA, Spanaki C, Griffith A, et al. Haplotype analysis of Lrrk2 R1441H carriers with parkinsonism. Parkinsonism Relat Disord 2009;15:466-467.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Zhang L, Quadri M, Guedes LC, et al. Comprehensive LRRK2 and GBA screening in Portuguese patients with Parkinson's disease: identification of a new family with the LRRK2 p.Arg1441His mutation and novel missense variants. Parkinsonism Relat Disord 2013;19:897-900.PubMedGoogle Scholar
  86. 86.
    Puschmann A. Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations. Parkinsonism Relat Disord 2013;19:407-415.PubMedGoogle Scholar
  87. 87.
    Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, Cookson MR. Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proc Natl Acad Sci U S A 2008;105:1499-1504.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Daniels V, Vancraenenbroeck R, Law BM, et al. Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant. J Neurochem 2011;116:304-315.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Liao J, Wu CX, Burlak C, et al. Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain. Proc Natl Acad Sci U S A 2014;111:4055-4060.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Li Y, Dunn L, Greggio E, et al. The R1441C mutation alters the folding properties of the ROC domain of LRRK2. Biochim Biophys Acta 2009;1792:1194-1197.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Gotthardt K, Weyand M, Kortholt A, Van Haastert PJ, Wittinghofer A. Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase. EMBO J 2008;27:2239-2249PubMedPubMedCentralGoogle Scholar
  92. 92.
    Lobbestael E, Zhao J, Rudenko IN, et al. Identification of protein phosphatase 1 as a regulator of the LRRK2 phosphorylation cycle. Biochem J 2013;456:119-128.PubMedGoogle Scholar
  93. 93.
    Kim JM, Lee JY, Kim HJ, et al. The LRRK2 G2385R variant is a risk factor for sporadic Parkinson's disease in the Korean population. Parkinsonism Relat Disord 2010;16:85-88.PubMedGoogle Scholar
  94. 94.
    Tan EK, Zhao Y, Skipper L, et al. The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Hum Genet 2007;120:857-863.PubMedGoogle Scholar
  95. 95.
    Fu X, Zheng Y, Hong H, et al. LRRK2 G2385R and LRRK2 R1628P increase risk of Parkinson's disease in a Han Chinese population from Southern Mainland China. Parkinsonism Relat Disord 2013;19:397-398.PubMedGoogle Scholar
  96. 96.
    Fung HC, Chen CM, Hardy J, Singleton AB, Wu YR. A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan. BMC Neurol 2006;6:47.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Funayama M, Li Y, Tomiyama H, et al. Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population. Neuroreport 2007;18:273-275.PubMedGoogle Scholar
  98. 98.
    Ross OA, Wu YR, Lee MC, et al. Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease. Ann Neurol 2008;64:88-92.PubMedGoogle Scholar
  99. 99.
    Tan EK, Tan LC, Lim HQ, et al. LRRK2 R1628P increases risk of Parkinson's disease: replication evidence. Hum Genet 2008;124:287-288.PubMedGoogle Scholar
  100. 100.
    Yu L, Hu F, Zou X, et al. LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China. Brain Res 2009;1296:113-116.PubMedGoogle Scholar
  101. 101.
    Zhang Z, Burgunder JM, An X, et al. LRRK2 R1628P variant is a risk factor of Parkinson's disease among Han-Chinese from mainland China. Mov Disord 2009;24:1902-1905.PubMedGoogle Scholar
  102. 102.
    Ross OA, Soto-Ortolaza AI, Heckman MG, et al. Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: a case–control study. Lancet Neurol 2011;10:898-908.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Jorgensen ND, Peng Y, Ho CC, et al. The WD40 domain is required for LRRK2 neurotoxicity. PLoS One 2009;4:e8463.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Puschmann A, Englund E, Ross OA, et al. First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation. Parkinsonism Relat Disord 2012;18:332-338.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Sheng Z, Zhang S, Bustos D, et al. Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci Transl Med 2012;4:164ra1.Google Scholar
  106. 106.
    Chen L, Zhang S, Liu Y, et al. LRRK2 R1398H polymorphism is associated with decreased risk of Parkinson's disease in a Han Chinese population. Parkinsonism Relat Disord 2011;17:291-292.PubMedGoogle Scholar
  107. 107.
    Tan EK, Peng R, Teo YY, et al. Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study. Hum Mutat 2010;31:561-568.PubMedGoogle Scholar
  108. 108.
    Rubio JP, Topp S, Warren L, et al. Deep sequencing of the LRRK2 gene in 14,002 individuals reveals evidence of purifying selection and independent origin of the p.Arg1628Pro mutation in Europe. Hum Mutat 2012;33:1087-1098.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Heckman MG, Elbaz A, Soto-Ortolaza AI, et al. The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. Neurobiol Aging 2014;35:266 e5- e14.Google Scholar
  110. 110.
    Biosa A, Trancikova A, Civiero L, et al. GTPase activity regulates kinase activity and cellular phenotypes of Parkinson's disease-associated LRRK2. Hum Mol Genet 2013;22:1140-1156.PubMedGoogle Scholar
  111. 111.
    Xiong Y, Coombes CE, Kilaru A, et al. GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genet 2010;6:e1000902.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Skibinski G, Nakamura K, Cookson MR, Finkbeiner S. Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. J Neurosci 2014;34:418-433.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Lee BD, Shin JH, VanKampen J, et al. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nat Med 2010;16:998-1000.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Liu Z, Wang X, Yu Y, et al. A Drosophila model for LRRK2-linked parkinsonism. Proc Natl Acad Sci U S A 2008;105:2693-2698.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Lin CH, Tsai PI, Wu RM, Chien CT. LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3ss. J Neurosci 2010;30:13138-13149.PubMedGoogle Scholar
  116. 116.
    Liu Z, Hamamichi S, Lee BD, et al. Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models. Hum Mol Genet 2011;20:3933-3942.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Ng CH, Mok SZ, Koh C, et al. Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. J Neurosci 2009;29:11257-11262.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Martin I, Kim JW, Lee BD, et al. Ribosomal protein s15 phosphorylation mediates lrrk2 neurodegeneration in Parkinson's disease. Cell 2014;157:472-485.PubMedGoogle Scholar
  119. 119.
    Trancikova A, Mamais A, Webber PJ, et al. Phosphorylation of 4E-BP1 in the mammalian brain is not altered by LRRK2 expression or pathogenic mutations. PLoS One 2012;7:e47784.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Yao C, El Khoury R, Wang W, et al. LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease. Neurobiol Dis 2010;40:73-81.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Saha S, Guillily MD, Ferree A, et al. LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci 2009;29:9210-9218.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Venderova K, Kabbach G, Abdel-Messih E, et al. Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease. Hum Mol Genet 2009;18:4390-4404.PubMedGoogle Scholar
  123. 123.
    Dusonchet J, Kochubey O, Stafa K, et al. A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2. J Neurosci 2011;31:907-912.PubMedGoogle Scholar
  124. 124.
    Ramonet D, Daher JP, Lin BM, et al. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 2011;6:e18568.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Chen CY, Weng YH, Chien KY, et al. (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell Death Differ 2012;19:1623-1633.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Maekawa T, Mori S, Sasaki Y, et al. The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities. Mol Neurodegener 2012;7:15.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Li Y, Liu W, Oo TF, et al. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci 2009;12:826-828.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Dranka BP, Gifford A, Ghosh A, et al. Diapocynin prevents early Parkinson's disease symptoms in the leucine-rich repeat kinase 2 (LRRK2R(1)(4)(4)(1)G) transgenic mouse. Neurosci Lett 2013;549:57-62.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Tong Y, Pisani A, Martella G, et al. R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proc Natl Acad Sci U S A 2009;106:14622-14627.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Higashi S, Biskup S, West AB, et al. Localization of Parkinson's disease-associated LRRK2 in normal and pathological human brain. Brain Res 2007;1155:208-219.PubMedGoogle Scholar
  131. 131.
    Higashi S, Moore DJ, Colebrooke RE, et al. Expression and localization of Parkinson's disease-associated leucine-rich repeat kinase 2 in the mouse brain. J Neurochem 2007;100:368-381.PubMedGoogle Scholar
  132. 132.
    Galter D, Westerlund M, Carmine A, Lindqvist E, Sydow O, Olson L. LRRK2 expression linked to dopamine-innervated areas. Ann Neurol 2006;59:714-719.PubMedGoogle Scholar
  133. 133.
    Melrose H, Lincoln S, Tyndall G, Dickson D, Farrer M. Anatomical localization of leucine-rich repeat kinase 2 in mouse brain. Neuroscience 2006;139:791-794.PubMedGoogle Scholar
  134. 134.
    Taymans JM, Van den Haute C, Baekelandt V. Distribution of PINK1 and LRRK2 in rat and mouse brain. J Neurochem 2006;98:951-961.PubMedGoogle Scholar
  135. 135.
    Miklossy J, Arai T, Guo JP, et al. LRRK2 expression in normal and pathologic human brain and in human cell lines. J Neuropathol Exp Neurol 2006;65:953-963.PubMedGoogle Scholar
  136. 136.
    Dachsel JC, Behrouz B, Yue M, Beevers JE, Melrose HL, Farrer MJ. A comparative study of Lrrk2 function in primary neuronal cultures. Parkinsonism Relat Disord 2010;16:650-655.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Chan D, Citro A, Cordy JM, Shen GC, Wolozin B. Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2). J Biol Chem 2011;286:16140-16149.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Kawakami F, Yabata T, Ohta E, et al. LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth. PLoS One 2012;7:e30834.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Ujiie S, Hatano T, Kubo S, et al. LRRK2 I2020T mutation is associated with tau pathology. Parkinsonism Relat Disord 2012;18:819-823.PubMedGoogle Scholar
  140. 140.
    Plowey ED, Cherra SJ, 3rd, Liu YJ, Chu CT. Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 2008;105:1048-1056.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Biskup S, Moore DJ, Celsi F, et al. Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol 2006;60:557-569.PubMedGoogle Scholar
  142. 142.
    Alegre-Abarrategui J, Christian H, Lufino MM, et al. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 2009;18:4022-4034.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Dodson MW, Zhang T, Jiang C, Chen S, Guo M. Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning. Hum Mol Genet 2012;21:1350-1363.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Zimprich A, Benet-Pages A, Struhal W, et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet 2011;89:168-175.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Vilarino-Guell C, Wider C, Ross OA, et al. VPS35 mutations in Parkinson disease. Am J Hum Genet 2011;89:162-167.PubMedPubMedCentralGoogle Scholar
  146. 146.
    Manzoni C, Mamais A, Dihanich S, et al. Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation. Biochem Biophys Res Commun 2013;441:862-866.PubMedPubMedCentralGoogle Scholar
  147. 147.
    Sakaguchi-Nakashima A, Meir JY, Jin Y, Matsumoto K, Hisamoto N. LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Curr Biol 2007;17:592-598.PubMedGoogle Scholar
  148. 148.
    Cukierman E, Huber I, Rotman M, Cassel D. The ARF1 GTPase-activating protein: zinc finger motif and Golgi complex localization. Science 1995;270:1999-2002.PubMedGoogle Scholar
  149. 149.
    McMahon HT, Mills IG. COP and clathrin-coated vesicle budding: different pathways, common approaches. Curr Opin Cell Biol 2004;16:379-391.PubMedGoogle Scholar
  150. 150.
    Lin X, Parisiadou L, Gu XL, et al. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 2009;64:807-827.PubMedPubMedCentralGoogle Scholar
  151. 151.
    Beilina A, Rudenko IN, Kaganovich A, et al. Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc Natl Acad Sci U S A 2014;111:2626-2631.PubMedPubMedCentralGoogle Scholar
  152. 152.
    Shin N, Jeong H, Kwon J, et al. LRRK2 regulates synaptic vesicle endocytosis. Exp Cell Res 2008;314:2055-2065.PubMedGoogle Scholar
  153. 153.
    Cooper O, Seo H, Andrabi S, et al. Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease. Sci Transl Med 2012;4:141ra90.Google Scholar
  154. 154.
    Sanders LH, Laganiere J, Cooper O, et al. LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction. Neurobiol Dis 2014;62:381-386.PubMedGoogle Scholar
  155. 155.
    Mortiboys H, Johansen KK, Aasly JO, Bandmann O. Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2. Neurology 2010;75:2017-2020.PubMedGoogle Scholar
  156. 156.
    Vancraenenbroeck R, Lobbestael E, Maeyer MD, Baekelandt V, Taymans JM. Kinases as targets for Parkinson's disease: from genetics to therapy. CNS Neurol Disord Drug Targets 2011;10:724-740.PubMedGoogle Scholar
  157. 157.
    Ramsden N, Perrin J, Ren Z, et al. Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons. ACS Chem Biol 2011;6:1021-1028.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Deng X, Dzamko N, Prescott A, et al. Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat Chem Biol 2011;7:203-205.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Kramer T, Lo Monte F, Goring S, Okala Amombo GM, Schmidt B. Small molecule kinase inhibitors for LRRK2 and their application to Parkinson's disease models. ACS Chem Neurosci 2012;3:151-160.PubMedPubMedCentralGoogle Scholar
  160. 160.
    Choi HG, Zhang J, Deng X, et al. Brain penetrant LRRK2 inhibitor. ACS Med Chem Lett 2012;3:658-662.PubMedPubMedCentralGoogle Scholar
  161. 161.
    Troxler T, Greenidge P, Zimmermann K, et al. Discovery of novel indolinone-based, potent, selective and brain penetrant inhibitors of LRRK2. Bioorg Med Chem Lett 2013;23:4085-90.PubMedGoogle Scholar
  162. 162.
    Estrada AA, Liu X, Baker-Glenn C, et al. Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem 2012;55:9416-9433.PubMedGoogle Scholar
  163. 163.
    Westerlund M, Belin AC, Anvret A, Bickford P, Olson L, Galter D. 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 2008;152:429-436.PubMedGoogle Scholar
  164. 164.
    Rudenko IN, Chia R, Cookson MR. Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease? BMC Med 2012;10:20.PubMedPubMedCentralGoogle Scholar
  165. 165.
    Lee BD, Dawson VL, Dawson TM. Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson's disease. Trends Pharmacol Sci 2012;33:365-373.PubMedPubMedCentralGoogle Scholar
  166. 166.
    Tain LS, Mortiboys H, Tao RN, Ziviani E, Bandmann O, Whitworth AJ. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat Neurosci 2009;12:1129-1135.PubMedPubMedCentralGoogle Scholar
  167. 167.
    Chartier-Harlin MC, Dachsel JC, Vilarino-Guell C, et al. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet 2011;89:398-406.PubMedPubMedCentralGoogle Scholar
  168. 168.
    Halliday GM, McCann H. The progression of pathology in Parkinson's disease. Ann N Y Acad Sci 2010;1184:188-195.PubMedGoogle Scholar
  169. 169.
    Latourelle JC, Sun M, Lew MF, et al. The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study. BMC Med 2008;6:32.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Goldwurm S, Zini M, Mariani L, et al. Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease. Neurology 2007;68:1141-1143.PubMedGoogle Scholar
  171. 171.
    Matta S, Van Kolen K, da Cunha R, et al. LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 2012;75:1008-1021.PubMedGoogle Scholar
  172. 172.
    Niu J, Yu M, Wang C, Xu Z. Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via Dynamin-like protein. J Neurochem 2012;122:650-658.PubMedGoogle Scholar
  173. 173.
    Wang X, Yan MH, Fujioka H, et al. LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet 2012;21:1931-1944.PubMedPubMedCentralGoogle Scholar
  174. 174.
    Law BM, Spain VA, Leinster VH, et al. A direct interaction between leucine-rich repeat kinase 2 and specific beta-tubulin isoforms regulates tubulin acetylation. J Biol Chem 2014;289:895-908.PubMedPubMedCentralGoogle Scholar
  175. 175.
    Bravo-San Pedro JM, Niso-Santano M, Gomez-Sanchez R, et al. The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway. Cell Mol Life Sci 2013;70:121-136.PubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. (outside the U.S.) 2014

Authors and Affiliations

  1. 1.Cell Biology and Gene Expression Section, Laboratory of NeurogeneticsNational Institute on Aging, National Institutes of HealthBethesdaUSA

Personalised recommendations