Targeting leucine-rich repeat kinase 2 in Parkinson's disease

Expert Opinion on Therapeutic Targets

Volumn 17, Issue 12, 2013, Pages 1471-1482

  Chan, Sharon L ^a   Angeles, Dario C ^b   Tan, Eng King ^a  

^a NATIONAL NEUROSCIENCE INSTITUTE   (Singapore)

^b SINGAPORE GENERAL HOSPITAL   (Singapore)

Author keywords

Autosomal dominant; Leucine rich repeat kinase; LRRK2; Multidomain protein; Parkinson's disease

Indexed keywords

BIOLOGICAL MARKER; LEUCINE RICH REPEAT KINASE 2; MULTIDOMAIN PROTEIN LRRK2; PROTEIN; TAU PROTEIN; UNCLASSIFIED DRUG;

AUTOPHAGY; CLEARANCE; DYNAMICS; ENZYME ACTIVITY; ENZYME INHIBITION; GENE; GENETICS; HOSPITAL SERVICE; HUMAN; LEWY BODY; MICROTUBULE; OXIDATIVE STRESS; PARKINSON DISEASE; PATHOPHYSIOLOGY; REGULATORY MECHANISM; REVIEW;

ANIMALS; BIOLOGICAL MARKERS; HUMANS; PARKINSON DISEASE; PROTEIN-SERINE-THREONINE KINASES;

EID: 84887945830     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2013.842978     Document Type: Review

References (119)

1. Prakash KM, Tan EK. Development of Parkinson's disease biomarkers. Expert Rev Neurother 2010;10(12):1811-25
2. Peeraully T, Tan EK. Genetic variants in sporadic Parkinson's disease: East vs West. Parkinsonism Relat Disord 2012;18(Suppl 1):S63-5
3. Jankovic J. Parkinson's disease: Clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79:368-76
4. Tan EK, Skipper LM. Pathogenic mutations in Parkinson disease. Hum Mutat 2007;28(7):641-53
5. 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
6. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601-7
7. Lu YW, Tan EK. Molecular biology changes associated with LRRK2 mutations in Parkinson's disease. J Neurosci Res 2008;86(9):1895-901
8. Bosgraaf L, Van Haastert PJ. Roc, a Ras/ GTPase domain in complex proteins. Biochim Biophys Acta 2003;1643:5-10
9. Kumari U, Tan EK. LRRK2 in Parkinson's disease: Genetic and clinical studies from patients. FEBS J 2009;276:6455-63
10. Wider C, Dickson DW, Wszolek ZK. Leucine-rich repeat kinase 2 gene-Associated disease: Redefining genotype-phenotype correlation. Neurodegener Dis 2010;7:175-9
11. Tan EK, Peng R, Teo YY, et al. Multiple LRRK2 variants modulate risk of Parkinson disease: A Chinese multicenter study. Hum Mutat 2010;31(5):561-8
12. Aasly JO, Vilarino-Guell C, Dachsel JC, et al. Novel pathogenic LRRK2 p. Asn1437His substitution in familial Parkinson's disease. Mov Disord 2010;25:2156-63
13. Tan EK. Rare and common LRRK2 exonic variants in Parkinson's disease. Lancet Neurol 2011;10(10):869-70
14. Kay DM, Kramer P, Higgins D, et al. Escaping Parkinson's disease: A neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov Disord 2005;20:1077-8
15. Clark LN, Wang Y, Karlins E, et al. Frequency of LRRK2 mutations in earlyand late-onset Parkinson disease. Neurology 2006;67:1786-91
16. Melrose H. Update on the functional biology of Lrrk2. Future Neurol 2008;3:669-81
17. Gehrke S, Imai Y, Sokol N, Lu B. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 2010;466:637-41
18. 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;27:2432-43
19. Gandhi PN, Wang X, Zhu X, et al. The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules. J Neurosci Res 2008;86:1711-20
20. Caesar M, Zach S, Carlson CB, et al. Leucine-rich repeat kinase 2 functionally interacts with microtubules and kinase-dependently modulates cell migration. Neurobiol Dis 2013;54:280-8
21. 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;110:1514-22
22. 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
23. Lee S, Liu HP, Lin WY, et al. LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction. J Neurosci 2010;30:16959-69
24. Kett LR, Boassa D, Ho CC, et al. LRRK2 Parkinson disease mutations enhance its microtubule association. Hum Mol Genet 2012;21:890-9
25. Matta S, Van Kolen K, da Cunha R, et al. LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 2012;75:1008-21
26. Dodson MW, Zhang T, Jiang C, et al. Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning. Hum Mol Genet 2012;21:1350-63
27. MacLeod DA, Rhinn H, Kuwahara T, et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 2013;77:425-39
28. Gomez-Suaga P, Churchill GC, Patel S, Hilfiker S. A link between LRRK2, autophagy and NAADP-mediated endolysosomal calcium signalling. Biochem Soc Trans 2012;40:1140-6
29. Plowey ED, Cherra SJ III, Liu YJ, Chu CT. Role of autophagy in G2019S-LRRK2-Associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 2008;105:1048-56
30. 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;70:121-36
31. Wang D, Zhang Z, O'Loughlin E, et al. Quantitative functions of Argonaute proteins in mammalian development. Genes Dev 2012;26:693-704
32. Gehrke S, Imai Y, Sokol N, Lu B. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 2010;466:637-41
33. Biswas AK, Johnson DG. Transcriptional and nontranscriptional functions of E2F1 in response to DNA damage. Cancer Res 2012;72:13-17
34. 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
35. Gillardon F. Interaction of elongation factor 1-Alpha with leucine-rich repeat kinase 2 impairs kinase activity and microtubule bundling in vitro. Neuroscience 2009;163:533-9
36. Munshi R, Kandl KA, Carr-Schmid A, et al. Overexpression of translation elongation factor 1A affects the organization and function of the actin cytoskeleton in yeast. Genetics 2001;157:1425-36
37. Takemura R, Okabe S, Umeyama T, et al. Increased microtubule stability and alpha tubulin acetylation in cells transfected with microtubule-Associated proteins MAP1B, MAP2 or tau. J Cell Sci 1992;103(Pt 4):953-64
38. Black MM, Slaughter T, Fischer I. Microtubule-Associated protein 1b (MAP1b) is concentrated in the distal region of growing axons. J Neurosci 1994;14:857-70
39. Tortosa E, Montenegro-Venegas C, Benoist M, et al. Microtubule-Associated protein 1B (MAP1B) is required for dendritic spine development and synaptic maturation. J Biol Chem 2011;286:40638-48
40. Bettencourt da Cruz A, Schwarzel M, Schulze S, et al. Disruption of the MAP1B-related protein FUTSCH leads to changes in the neuronal cytoskeleton, axonal transport defects, and progressive neurodegeneration in Drosophila. Mol Biol Cell 2005;16:2433-42
41. Cartelli D, Goldwurm S, Casagrande F, et al. Microtubule destabilization is shared by genetic and idiopathic Parkinson's disease patient fibroblasts. PLoS One 2012;7:e37467
42. Mackeh R, Perdiz D, Lorin S, et al. Autophagy and microtubules - new story, old players. J Cell Sci 2013;126:1071-80
43. 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 2005;102:16842-7
44. Biskup S, Moore DJ, Celsi F, et al. Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol 2006;60:557-69
45. 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;15:223-32
46. Hatano T, Kubo S, Imai S, et al. Leucine-rich repeat kinase 2 associates with lipid rafts. Hum Mol Genet 2007;16:678-90
47. Ringstad N, Nemoto Y, De Camilli P. The SH3p4/Sh3p8/SH3p13 protein family: Binding partners for synaptojanin and dynamin via a Grb2-like Src homology 3 domain. Proc Natl Acad Sci USA 1997. 94:8569-74
48. Shin N, Jeong H, Kwon J, et al. LRRK2 regulates synaptic vesicle endocytosis. Exp Cell Res 2008;314:2055-65
49. Carney DS, Davies BA, Horazdovsky BF. Vps9 domain-containing proteins: Activators of Rab5 GTPases from yeast to neurons. Trends Cell Biol 2006;16:27-35
50. Wucherpfennig T, Wilsch-Brauninger M, Gonzalez-Gaitan M. Role of Drosophila Rab5 during endosomal trafficking at the synapse and evoked neurotransmitter release. J Cell Biol 2003;161:609-24
51. Rink J, Ghigo E, Kalaidzidis Y, Zerial M. Rab conversion as a mechanism of progression from early to late endosomes. Cell 2005;122:735-49
52. Cherra SJ III, Steer E, Gusdon AM, et al. Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol 2013;182:474-84
53. Orenstein SJ, Kuo SH, Tasset I, et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 2013;16:394-406
54. Friedman LG, Lachenmayer ML, Wang J, et al. Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J Neurosci 2012;32:7585-93
55. 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 USA 2010;107:9879-84
56. Gonzalez-Fernandez MC, Lezcano E, Ross OA, et al. Lrrk2-Associated parkinsonism is a major cause of disease in Northern Spain. Parkinsonism Relat Disord 2007;13:509-15
57. Lesage S, Durr A, Tazir M, et al. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med 2006;354:422-3
58. 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;354:424-5
59. Poulopoulos M, Levy OA, Alcalay RN. The neuropathology of genetic Parkinson's disease. Mov Disord 2012;27:831-42
60. Cookson MR, Hardy J, Lewis PA. Genetic neuropathology of Parkinson's disease. Int J Clin Exp Pathol 2008;1:217-31
61. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004;305:626-9
62. Luoma P, Melberg A, Rinne JO, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: Clinical and molecular genetic study. Lancet 2004;364:875-82
63. Davidzon G, Greene P, Mancuso M, et al. Early-onset familial parkinsonism due to POLG mutations. Ann Neurol 2006;59:859-62
64. Angeles DC, Gan BH, Onstead L, et al. Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. Hum Mutat 2011;32:1390-7
65. Nguyen HN, Byers B, Cord B, et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 2011;8:267-80
66. Liu GH, Qu J, Suzuki K, et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 2012;491:603-7
67. McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop: Diagnosis and treatment. Consortium on Dementia with Lewy Bodies. Neurology 1999. 53:902-5
68. Zhu X, Siedlak SL, Smith MA, et al. LRRK2 protein is a component of Lewy bodies. Ann Neurol 2006;60:617-18.author reply 8-9
69. Jensen PH, Islam K, Kenney J, et al. Microtubule-Associated protein 1B is a component of cortical Lewy bodies and binds alpha-synuclein filaments. J Biol Chem 2000;275:21500-7
70. Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature 1997;388:839-40
71. Guerreiro PS, Huang Y, Gysbers A, et al. LRRK2 interactions with alpha-synuclein in Parkinson's disease brains and in cell models. J Mol Med 2013;91:513-22
72. Kuwahara T, Tonegawa R, Ito G, et al. Phosphorylation of alpha-synuclein protein at Ser-129 reduces neuronal dysfunction by lowering its membrane binding property in Caenorhabditis elegans. J Biol Chem 2012;287:7098-109
73. Auluck PK, Caraveo G, Lindquist S. alpha-Synuclein: Membrane interactions and toxicity in Parkinson's disease. Annu Rev Cell Dev Biol 2010;26:211-33
74. Kanao T, Venderova K, Park DS, et al. Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila. Hum Mol Genet 2010;19:3747-58
75. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 1975;72:1858-62
76. Rhodes SL, Sinsheimer JS, Bordelon Y, et al. Replication of GWAS associations for GAK and MAPT in Parkinson's disease. Ann Hum Genet 2011;75:195-200
77. Ujiie S, Hatano T, Kubo S, et al. LRRK2 I2020T mutation is associated with tau pathology. Parkinsonism Relat Disord 2012;18:819-23
78. Ling H, Kara E, Bandopadhyay R, et al. TDP-43 pathology in a patient carrying G2019S LRRK2 mutation and a novel p. Q124E MAPT. Neurobiol Aging 2013
79. Xu Q, Shenoy S, Li C. Mouse models for LRRK2 Parkinson's disease. Parkinsonism Relat Disord 2012;18(Suppl 1):S186-9
80. International Parkinson Disease Genomics C. Nalls MA, Plagnol V, Hernandez DG, et al. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: A meta-Analysis of genome-wide association studies. Lancet 2011;377:641-9
81. 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;41:1303-7
82. 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
83. Greggio E, Jain S, Kingsbury A, et al. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 2006;23:329-41
84. 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
85. Heo HY, Park JM, Kim CH, et al. LRRK2 enhances oxidative stress-induced neurotoxicity via its kinase activity. Exp Cell Res 2010;316:649-56
86. Zhao J, Hermanson SB, Carlson CB, et al. Pharmacological inhibition of LRRK2 cellular phosphorylation sites provides insight into LRRK2 biology. Biochem Soc Trans 2012;40:1158-62
87. 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;430:405-13
88. 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;20:3933-42
89. Yun H, Heo HY, Kim HH, et al. Identification of chemicals to inhibit the kinase activity of leucine-rich repeat kinase 2 (LRRK2), a Parkinson's disease-Associated protein. Bioorg Med Chem Lett 2011;21:2953-7
90. Deng X, Dzamko N, Prescott A, et al. Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat Chem Biol 2011;7:203-5
91. 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;6:1021-8
92. Choi HG, Zhang J, Deng X, et al. Brain penetrant LRRK2 inhibitor. ACS Med Chem Lett 2012;3:658-62
93. Chen H, Chan BK, Drummond J, et al. Discovery of selective LRRK2 inhibitors guided by computational analysis and molecular modeling. J Med Chem 2012;55:5536-45
94. Deng X, S Gray N. Pyrazolopyridines as inhibitors of the kinase LRRK2: A patent evaluation (WO2011141756). Expert Opin Ther Patents 2012.22:709-13
95. 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
96. Ravikumar B, Imarisio S, Sarkar S, et al. Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J Cell Sci 2008;121:1649-60
97. Ganley IG, Wong PM, Gammoh N, Jiang X. Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol Cell 2011;42:731-43
98. Ness D, Ren Z, Gardai S, et al. Leucine-rich repeat kinase 2 (LRRK2)- deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. PLoS One 2013;8:e66164
99. Dachsel JC, Farrer MJ. LRRK2 and Parkinson disease. Arch Neurol 2010;67:542-7
100. Biomarkers Definitions Working G. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89-95
101. Sharma S, Moon CS, Khogali A, et al. Biomarkers in Parkinson's disease (recent update). Neurochem Int 2013;63:201-29
102. Gorostidi A, Bergareche A, Ruiz-Martinez J, et al. Alphalpha-synuclein levels in blood plasma from LRRK2 mutation carriers. PloS One 2012;7:e52312
103. Aasly JO, Shi M, Sossi V, et al. Cerebrospinal fluid amyloid beta and tau in LRRK2 mutation carriers. Neurology 2012;78:55-61
104. Shi M, Furay AR, Sossi V, et al. DJ-1 and alphaSYN in LRRK2 CSF do not correlate with striatal dopaminergic function. Neurobiol Aging 2012;33:836 e5-7
105. Van Nuenen BF, Helmich RC, Ferraye M, et al. Cerebral pathological and compensatory mechanisms in the premotor phase of leucine-rich repeat kinase 2 parkinsonism. Brain 2012;135:3687-98
106. Sierra M, Sanchez-Juan P, Martinez-Rodriguez MI, et al. Olfaction and imaging biomarkers in premotor LRRK2 G2019S-Associated Parkinson disease. Neurology 2013;80:621-6
107. Parnetti L, Castrioto A, Chiasserini D, et al. Cerebrospinal fluid biomarkers in Parkinson disease. Nat Rev Neurol 2013;9:131-40
108. Lytton J, Westlin M, Hanley MR. Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J Biol Chem 1991;266:17067-71
109. Lewis PA, Greggio E, Beilina A, et al. The R1441C mutation of LRRK2 isrupts GTP hydrolysis. Biochem Biophys Res Commun 2007;357:668-71
110. 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 2007;103:238-47
111. Daniels V, Vancraenenbroeck R, Law BM, et al. Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant. J Neurochem 2011;116:304-15
112. 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;405:307-17
113. Smith WW, Pei Z, Jiang H, et al. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 2006;9:1231-3
114. Ohta E, Hasegawa K, Gasser T, Obata F. Independent occurrence of I2020T mutation in the kinase domain of the leucine rich repeat kinase 2 gene in Japanese and German Parkinson's disease families. Neurosci Lett 2007;417:21-3
115. 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 2007;16:223-32
116. 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
117. Mata IF, Kachergus JM, Taylor JP, et al. Lrrk2 pathogenic substitutions in Parkinson's disease. Neurogenetics 2005;6:171-7
118. Di Fonzo A, Rohe CF, Ferreira J, et al. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 2005;365:412-15
119. Zabetian CP, Samii A, Mosley AD, et al. A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations. Neurology 2005;65:741-4