Current understanding of LRRK2 in Parkinsons disease: Biochemical and structural features and inhibitor design

Future Medicinal Chemistry

Volumn 4, Issue 13, 2012, Pages 1701-1713

  Ray, Soumya ^a   Liu, Min ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SYNUCLEIN; BOSUTINIB; ENZYME INHIBITOR; IMATINIB; LEUCINE RICH REPEAT KINASE 2; LEUCINE RICH REPEAT KINASE 2 INHIBITOR; PONATINIB; SORAFENIB; TAU PROTEIN; UNCLASSIFIED DRUG;

AUTOPHAGY; DRUG ACTIVITY; DRUG RESEARCH; ENZYME ACTIVITY; ENZYME ANALYSIS; ENZYME INHIBITION; ENZYME REGULATION; HUMAN; NONHUMAN; PARKINSON DISEASE; PATHOGENESIS; PRIORITY JOURNAL; REVIEW;

ANIMALS; DRUG DISCOVERY; HUMANS; MODELS, MOLECULAR; MOLECULAR TARGETED THERAPY; PARKINSON DISEASE; PROTEIN CONFORMATION; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES;

EID: 84865788193     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.12.110     Document Type: Review

References (88)

1. Paisan-Ruiz C, Jain S, Evans EW et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600 (2004).
2. Zimprich A, Biskup S, Leitner P et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607 (2004).
3. Berg D, Schweitzer KJ, Leitner P et al. Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease. Brain 128, 3000-3011 (2005).
4. Farrer M, Stone J, Mata IF et al. LRRK2 mutations in Parkinson disease. Neurology 65, 738-740 (2005).
5. Khan NL, Jain S, Lynch JM et al. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 128, 2786-2796 (2005).
6. 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. 100, 368-381 (2007).
7. Anand VS, Reichling LJ, Lipinski K et al. Investigation of leucine-rich repeat kinase 2: enzymological properties and novel assays. FEBS J. 276, 466-478 (2009).
8. 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. 65, 953-963 (2006).
9. Stafa K, Trancikova A, Webber PJ et al. GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet. 8, e1002526 (2012).
10. 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. 32, 3877-3886 (2012).
11. 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. 29, 13971-13980 (2009).
12. 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. 110, 1514-1522 (2009).
13. Imai Y, Gehrke S, Wang HQ et al. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J. 27, 2432-2443 (2008).
14. Gloeckner CJ, Schumacher A, Boldt K, Ueffing M. The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro. J. Neurochem. 109, 959-968 (2009).
15. Hsu CH, Chan D, Greggio E et al. MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2. J. Neurochem. 112, 1593-1604 (2010).
16. Qing H, Wong W, McGeer EG, McGeer PL. Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications. Biochem. Biophys. Res. Commun. 387, 149-152 (2009).
17. Angeles DC, Gan BH, Onstead L et al. Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. Hum. Mutat. 32, 1390-1397 (2011).
18. Ohta E, Kawakami F, Kubo M, Obata F. 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 (2011).
19. Tong Y, Giaime E, Yamaguchi H et al. Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol. Neurodegener. 7, 2 (2012).
20. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol. Med. 4, 380-395 (2012).
21. Ferree A, Guillily M, Li H et al. Regulation of physiologic actions of LRRK2: focus on autophagy. Neurodegener. Dis. 10, 238-241 (2012).
22. Kim B, Yang MS, Choi D et al. Impaired inflammatory responses in murine Lrrk2- knockdown brain microglia. PLoS ONE 7, e34693 (2012).
23. Gillardon F, Schmid R, Draheim H. Parkinson's disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity. Neuroscience 208, 41-48 (2012).
24. Botta-Orfila T, Sanchez-Pla A, Fernandez M et al. Brain transcriptomic profiling in idiopathic and LRRK2-associated Parkinson's disease. Brain Res. 1466, 152-157 (2012).
25. Moehle MS, Webber PJ, Tse T et al. LRRK2 inhibition attenuates microglial inflammatory responses. J. Neurosci. 32, 1602-1611 (2012).
26. Seol W. Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease. BMB Rep. 43, 233-244 (2010).
27. Yue Z. Genetic mouse models for understanding LRRK2 biology, pathology and pre-clinical application. Parkinsonism Relat. Disord. 18(Suppl. 1), S180-S182 (2012).
28. Cookson MR. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat. Rev. Neurosci. 11, 791-797 (2010).
29. Marin I, van Egmond WN, van Haastert PJ. The Roco protein family: a functional perspective. FASEB J. 22, 3103-3110 (2008).
30. 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 49, 5511-5523 (2010).
31. de Vet E, Gebhardt WA, Sinnige J et al. Implementation intentions for buying, carrying, discussing and using condoms: the role of the quality of plans. Health Educ. Res. 26, 443-455 (2011).
32. Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA. LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci. 29, 286-293 (2006).
33. Lewis PA, Manzoni C. LRRK2 and human disease: a complicated question or a question of complexes? Sci. Signal. 5(207), pe2 (2012).
34. 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. 283, 16906-16914 (2008).
35. 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. 27, 2239-2249 (2008).
36. Bennett MJ, Schlunegger MP, Eisenberg D. 3D domain swapping: a mechanism for oligomer assembly. Protein Sci. 4, 2455-2468 (1995).
37. Guo L, Gandhi PN, Wang W et al. The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Exp. Cell Res. 313, 3658-3670 (2007).
38. 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 49, 2008-2017 (2010).
39. Braconi Quintaje S, Orchard S. The annotation of both human and mouse kinomes in UniProtKB/Swiss-Prot: one small step in manual annotation, one giant leap for full comprehension of genomes. Mol. Cell. Proteomics 7, 1409-1419 (2008).
40. Manning G, Plowman GD, Hunter T, Sudarsanam S. Evolution of protein kinase signaling from yeast to man. Trends Biochem. Sci. 27, 514-520 (2002).
41. Meylan E, Tschopp J. The RIP kinases: crucial integrators of cellular stress. Trends Biochem. Sci. 30, 151-159 (2005).
42. Liu M, Kang S, Ray S et al. Kinetic, mechanistic, and structural modeling studies of truncated wild-type leucine-rich repeat kinase 2 and the G2019S mutant. Biochemistry 50, 9399-9408 (2011).
43. Taylor SS, Kornev AP. Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem. Sci. 36, 65-77 (2011).
44. Nichols RJ, Dzamko N, Morrice NA et al. 14-13-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochem. J. 430, 393-404 (2010).
45. 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. USA 102, 16842-16847 (2005).
46. Winner B, Melrose HL, Zhao C et al. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol. Dis. 41, 706-716 (2011).
47. Reichling LJ, Riddle SM. Leucine-rich repeat kinase 2 mutants I2020T and G2019S exhibit altered kinase inhibitor sensitivity. Biochem. Biophys. Res. Commun. 384, 255-258 (2009).
48. Gloeckner CJ, Kinkl N, Schumacher A et al. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum. Mol. Genet. 15, 223-232 (2006).
49. Greggio E, Jain S, Kingsbury A et al. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol. Dis. 23, 329-341 (2006).
50. 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. 16, 2031-2039 (2007).
51. Smith WW, Pei Z, Jiang H et al. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat. Neurosci. 9, 1231-1233 (2006).
52. Smith WW, Pei Z, Jiang H et al. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl Acad. Sci. USA 102, 18676-18681 (2005).
53. West AB, Moore DJ, Choi C et al. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet. 16, 223-232 (2007).
54. Avruch J, Zhang XF, Kyriakis JM. Raf meets Ras: completing the framework of a signal transduction pathway. Trends Biochem. Sci. 19, 279-283 (1994).
55. Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem. J. 351(Pt 2), 289-305 (2000).
56. Lewis PA, Greggio E, Beilina A et al. The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem. Biophys. Res. Commun. 357, 668-671 (2007).
57. 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 46, 1380-1388 (2007).
58. Webber PJ, Smith AD, Sen S et al. Autophosphorylation in the leucine-rich repeat kinase 2 (LRRK2) GTPase domain modifies kinase and GTP-binding activities. J. Mol. Biol. 412, 94-110 (2011).
59. Li X, Tan YC, Poulose S et al. 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 (2007).
60. 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 6, e23207 (2011).
61. 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. 9, 1738-1745 (2010).
62. Li X, Wang QJ, Pan N et al. Phosphorylation-dependent 14-13-3 binding to LRRK2 is impaired by common mutations of familial Parkinson's disease. PLoS ONE 6, e17153 (2011).
63. Deng X, Dzamko N, Prescott A et al. Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat. Chem. Biol. 7, 203-205 (2011).
64. Wang L, Xie C, Greggio E et al. 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 (2008).
65. Ko HS, Bailey R, Smith WW et al. CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proc. Natl Acad. Sci. USA 106, 2897-2902 (2009).
66. Kramer T, F Lo Monte, Amombo GMO, Schmidt B. Small molecule kinase inhibitors for LRRK2 and their application to Parkinson's disease models. ACS Chem. Neurosci. 3, 151-160 (2012).
67. Zhang J, Deng X, Choi HG, Alessi DR, Gray NS. Characterization of TAE684 as a potent LRRK2 kinase inhibitor. Bioorg. Med. Chem. Lett. 22, 1864-1869 (2012).
68. Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099-3108 (1973).
69. Lovitt B, Vanderporten EC, Sheng Z et al. Differential effects of divalent manganese and magnesium on the kinase activity of leucine-rich repeat kinase 2 (LRRK2). Biochemistry 49, 3092-3100 (2010).
70. Pedro L, Padros J, Beaudet L et al. Development of a high-throughput AlphaScreen assay measuring full-length LRRK2(G2019S) kinase activity using moesin protein substrate. Anal. Biochem. 404, 45-51 (2010).
71. Covy JP, Giasson BI. Identification of compounds that inhibit the kinase activity of leucine-rich repeat kinase 2. Biochem. Biophys. Res. Commun. 378, 473-477 (2009).
72. Liu M, Choi S, Cuny GD et al. Kinetic studies of Cdk5/p25 kinase: phosphorylation of tau and complex inhibition by two prototype inhibitors. Biochemistry 47, 8367-8377 (2008).
73. Wong H, Belvin M, Herter S et al. Pharmacodynamics of 2-[4-[(1E)-1- (hydroxyimino)-2,3-dihydro-1H-inden-5-yl]- 3-(pyridine-4-yl)-1H-pyraz ol-1-yl]ethan-1-ol (GDC-0879), a potent and selective B-Raf kinase inhibitor: understanding relationships between systemic concentrations, phosphorylated mitogen-activated protein kinase kinase 1 inhibition, and efficacy. J. Pharmacol. Exp. Ther. 329, 360-367 (2009).
74. Dzamko N, Deak M, Hentati F et al. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-13-3 binding and altered cytoplasmic localization. Biochem. J. 430, 405-413 (2010).
75. Covy JP, Yuan W, Waxman EA et al. Clinical and pathological characteristics of patients with leucine-rich repeat kinase-2 mutations. Mov. Disord. 24, 32-39 (2009).
76. 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. 41, 1303-1307 (2009).
77. Simon-Sanchez J, Schulte C, Bras JM et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308-1312 (2009).
78. Qing H, Zhang Y, Deng Y, McGeer EG, McGeer PL. LRRK2 interaction with alpha-synuclein in diffuse Lewy body disease. Biochem. Biophys. Res. Commun. 390, 1229-1234 (2009).
79. Devine MJ, Lewis PA. Emerging pathways in genetic Parkinson's disease: tangles, Lewy bodies and LRRK2. FEBS J. 275, 5748-5757 (2008).
80. 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 7, e30834 (2012).
81. 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. 105, 1048-1056 (2008).
82. 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 6, e18568 (2011).
83. Ferree A, Guillily M, Li H et al. Regulation of physiologic actions of LRRK2: focus on autophagy. Neurodegener. Dis. 10, 238-241 (2011).
84. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol. Med. 4, 380-395 (2012).
85. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305, 1292-1295 (2004).
86. Wang Y, Martinez-Vicente M, Kruger U et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum. Mol. Genet. 18, 4153-4170 (2009).
87. Dall'Armi C, Hurtado-Lorenzo A, Tian H et al. The phospholipase D1 pathway modulates macroautophagy. Nat. Commun. 1, 142 (2010).
88. Berger Z, Ravikumar B, Menzies FM et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433-442 (2006).