Targeting LRRK2 in Parkinson’s disease: an update on recent developments

Expert Opinion on Therapeutic Targets

Volumn 21, Issue 6, 2017, Pages 601-610

  Chan, Sharon L ^a   Tan, Eng King ^a  

^a NATIONAL NEUROSCIENCE INSTITUTE   (Singapore)

Author keywords

inhibitors; LRRK2; Parkinson s disease

Indexed keywords

LEUCINE RICH REPEAT KINASE 2; PHOSPHOTRANSFERASE INHIBITOR; RAB PROTEIN; ANTIPARKINSON AGENT; LRRK2 PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR;

AUTOPHAGY; CYTOSKELETON; ENZYME INHIBITION; ENZYME SUBSTRATE; EXPERIMENTAL MODEL; HUMAN; IMMUNOCOMPETENT CELL; INDUCED PLURIPOTENT STEM CELL; MITOCHONDRION; NONHUMAN; PARKINSON DISEASE; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG DESIGN; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOPHYSIOLOGY; PHENOTYPE;

ANIMALS; ANTIPARKINSON AGENTS; DRUG DESIGN; HUMANS; LEUCINE-RICH REPEAT SERINE-THREONINE PROTEIN KINASE-2; MOLECULAR TARGETED THERAPY; PARKINSON DISEASE; PHENOTYPE; PROTEIN KINASE INHIBITORS;

EID: 85019553951     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1080/14728222.2017.1323881     Document Type: Review

References (105)

1. Haugarvoll K, Rademakers R, Kachergus JM, et al. Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease. Neurology. 2008;70:1456–1460.
2. 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.
3. Foo JN, Chung SJ, Tan LC, et al. Linking a genome-wide association study signal to a LRRK2 coding variant in Parkinson’s disease. Mov Disord. 2016;31:484–487.
4. Foo JN, Tan LC, Irwan ID, et al. Genome-wide association study of Parkinson’s disease in East Asians. Hum Mol Genet. 2017;26:226–232.
5. Kumar PM, Paing SS, Li H, et al. Differential effect of caffeine intake in subjects with genetic susceptibility to Parkinson’s disease. Sci Rep. 2015;5:15492.
6. Oosterveld LP, Allen JC, Jr., Ng EY, et al. Greater motor progression in patients with Parkinson disease who carry LRRK2 risk variants. Neurology. 2015;85:1039–1042.
7. Tan EK., Rare and common LRRK2 exonic variants in Parkinson’s disease. Lancet Neurol. 2011;10:869–870.
8. Buhat DM, Tan EK. Genetic testing of LRRK2 in Parkinson’s disease:is there a clinical role? Parkinsonism Relat Disord. 2014;20(Suppl 1):S54–6.
9. Infante J, Prieto C, Sierra M, et al. Comparative blood transcriptome analysis in idiopathic and LRRK2 G2019S-associated Parkinson’s disease. Neurobiol Aging. 2016;38(214):e1–5.
10. 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.
11. 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.
12. Angeles DC, Ho P, Dymock BW, et al. Antioxidants inhibit neuronal toxicity in Parkinson’s disease-linked LRRK2. Ann Clin Transl Neurol. 2016;3:288–294.
13. Lu YW, Tan EK. Molecular biology changes associated with LRRK2 mutations in Parkinson’s disease. J Neurosci Res. 2008;86:1895–1901.
14. Angeles DC, Ho P, Chua LL, et al. Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila. Hum Mol Genet. 2014;23:3157–3165.
15. Chan SL, Angeles DC, Tan EK. Targeting leucine-rich repeat kinase 2 in Parkinson’s disease. Expert Opin Ther Targets. 2013;17:1471–1482.
16. Skibinski G, Nakamura K, Cookson MR, et al. Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. J Neurosci. 2014;34:418–433.
17. Doggett EA, Zhao J, Mork CN, et al. Phosphorylation of LRRK2 serines 955 and 973 is disrupted by Parkinson’s disease mutations and LRRK2 pharmacological inhibition. J Neurochem. 2012;120:37–45.
18. 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.
19. 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.
20. Dzamko N, Gysbers AM, Bandopadhyay R, et al. LRRK2 levels and phosphorylation in Parkinson’s disease brain and cases with restricted Lewy bodies. Mov Disord. 2017;32:423–432.
21. Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci. 2000;3:1301–1306.
22. Brooks AI, Chadwick CA, Gelbard HA, et al. Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res. 1999;823:1–10.
23. Carlsson A, Lindqvist M, Magnusson T. 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature. 1957;180:1200.
24. Heikkila RE, Nicklas WJ, Vyas I, et al. Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats:implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci Lett. 1985;62:389–394.
25. Przedborski S, Jackson-Lewis V, Naini AB, et al. The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP):a technical review of its utility and safety. J Neurochem. 2001;76:1265–1274.
26. Low K, Aebischer P. Use of viral vectors to create animal models for Parkinson’s disease. Neurobiol Dis. 2012;48:189–201.
27. 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.
28. 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.
29. Tsika E, Nguyen AP, Dusonchet J, et al. Adenoviral-mediated expression of G2019S LRRK2 induces striatal pathology in a kinase-dependent manner in a rat model of Parkinson’s disease. Neurobiol Dis. 2015;77:49–61.
30. Palomo-Garo C, Gomez-Galvez Y, Garcia C, et al. Targeting the cannabinoid CB2 receptor to attenuate the progression of motor deficits in LRRK2-transgenic mice. Pharmacol Res. 2016;110:181–192.
31. Hinkle KM, Yue M, Behrouz B, et al. LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors. Mol Neurodegener. 2012;7:25.
32. 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.
33. Baptista MA, Dave KD, Frasier MA, et al. Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs. Plos One. 2013;8:e80705.
34. 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.
35. Fell MJ, Mirescu C, Basu K, et al. MLi-2, a potent, selective, and centrally active compound for exploring the therapeutic potential and safety of LRRK2 kinase inhibition. J Pharmacol Exp Ther. 2015;355:397–409.
36. Daher JP, Abdelmotilib HA, Hu X, et al. Leucine-rich repeat kinase 2 (LRRK2) pharmacological inhibition abates alpha-synuclein gene-induced neurodegeneration. J Biol Chem. 2015;290:19433–19444.
37. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–872.
38. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–1920.
39. Lin T, Ambasudhan R, Yuan X, et al. A chemical platform for improved induction of human iPSCs. Nat Methods. 2009;6:805–808.
40. Okita K, Nakagawa M, Hyenjong H, et al. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008;322:949–953.
41. Stadtfeld M, Nagaya M, Utikal J, et al. Induced pluripotent stem cells generated without viral integration. Science. 2008;322:945–949.
42. Warren L, Manos PD, Ahfeldt T, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010;7:618–630.
43. Chambers SM, Fasano CA, Papapetrou EP, et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27:275–280.
44. Han DW, Tapia N, Hermann A, et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell. 2012;10:465–472.
45. Thier M, Worsdorfer P, Lakes YB, et al. Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell. 2012;10:473–479.
46. Nguyen HN, Byers B, Cord B, et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell. 2011;8:267–280.
47. Su YC, Qi X. Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet. 2013;22:4545–4561.
48. Orenstein SJ, Kuo SH, Tasset I, et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci. 2013;16:394–406.
49. 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.
50. Schwab AJ, Ebert AD. Neurite aggregation and calcium dysfunction in ipsc-derived sensory neurons with Parkinson’s disease-related LRRK2 G2019S mutation. Stem Cell Reports. 2015;5:1039–1052.
51. De Maturana L, Lang R,V, Zubiarrain A, et al. Mutations in LRRK2 impair NF-kappaB pathway in iPSC-derived neurons. J Neuroinflammation. 2016;13:295.
52. Ohta E, Nihira T, Uchino A, et al. I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3beta signaling pathway. Hum Mol Genet. 2015;24:4879–4900.• An interesting report depicting in vitro results from patient-derived iPSC and its corresponding postmortem pathology from the same patient.
53. 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.
54. Liu GH, Qu J, Suzuki K, et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature. 2012;491:603–607.
55. Choi HG, Zhang J, Deng X, et al. Brain penetrant LRRK2 inhibitor. ACS Med Chem Lett. 2012;3:658–662.
56. Reith AD, Bamborough P, Jandu K, et al. GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg Med Chem Lett. 2012;22:5625–5629.
57. Zhang J, Deng X, Choi HG, et al. Characterization of TAE684 as a potent LRRK2 kinase inhibitor. Bioorg Med Chem Lett. 2012;22:1864–1869.
58. Hatcher JM, Zhang J, Choi HG, et al. Discovery of a pyrrolopyrimidine (JH-II-127), a highly potent, selective, and brain penetrant LRRK2 inhibitor. ACS Med Chem Lett. 2015;6:584–589.
59. 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.
60. Fuji RN, Flagella M, Baca M, et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci Transl Med. 2015;7:273ra15.•• This study highlights the importance of examining the potential safety risks of LRRK2 inhibitors in complex mammalian models compared to the commonly used murine models.
61. Estrada AA, Chan BK, Baker-Glenn C, et al. Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem. 2014;57:921–936.
62. Henderson JL, Kormos BL, Hayward MM, et al. Discovery and preclinical profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J Med Chem. 2015;58:419–432.
63. 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;32:7585–7593.
64. 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.
65. Manzoni C, Mamais A, Roosen DA, et al. mTOR independent regulation of macroautophagy by leucine rich repeat kinase 2 via beclin-1. Sci Rep. 2016;6:35106.
66. Park S, Han S, Choi I, et al. Interplay between leucine-rich repeat kinase 2 (LRRK2) and p62/SQSTM-1 in selective autophagy. Plos One. 2016;11:e0163029.
67. Lobbestael E, Civiero L, De Wit T, et al. Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation. Sci Rep. 2016;6:33897.
68. Schapansky J, Nardozzi JD, Felizia F, et al. Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. Hum Mol Genet. 2014;23:4201–4214.
69. 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.
70. Rivero-Rios P, Gomez-Suaga P, Fernandez B, et al. Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked Parkinson’s disease. Biochem Soc Trans. 2015;43:390–395.
71. 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.
72. 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;161:609–624.
73. Shin N, Jeong H, Kwon J, et al. LRRK2 regulates synaptic vesicle endocytosis. Exp Cell Res. 2008;314:2055–2065.
74. Rink J, Ghigo E, Kalaidzidis Y, et al. Rab conversion as a mechanism of progression from early to late endosomes. Cell. 2005;122:735–749.
75. Dodson MW, Zhang T, Jiang C, et al. Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning. Hum Mol Genet. 2012;21:1350–1363.
76. Steger M, Tonelli F, Ito G, et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife. 2016;5.
77. Nichols RJ, Dzamko N, Hutti JE, et al. Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson’s disease. Biochem J. 2009;424:47–60.
78. Youle RJ, Van Der Bliek AM. Mitochondrial fission, fusion, and stress. Science. 2012;337:1062–1065.
79. 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.
80. Niu J, Yu M, Wang C, et al. Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via dynamin-like protein. J Neurochem. 2012;122:650–658.
81. Yang S, Xia C, Li S, et al. Mitochondrial dysfunction driven by the LRRK2-mediated pathway is associated with loss of Purkinje cells and motor coordination deficits in diabetic rat model. Cell Death Dis. 2014;5:e1217.
82. Stafa K, Tsika E, Moser R, et al. Functional interaction of Parkinson’s disease-associated LRRK2 with members of the dynamin GTPase superfamily. Hum Mol Genet. 2014;23:2055–2077.
83. Hsieh CH, Shaltouki A, Gonzalez AE, et al. Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell. 2016;19:709–724.
84. Choi I, Kim B, Byun JW, et al. LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase. Nat Commun. 2015;6:8255.
85. Godena VK, Brookes-Hocking N, Moller A, et al. Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat Commun. 2014;5:5245.
86. Civiero L, Cirnaru MD, Beilina A, et al. Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain. J Neurochem. 2015;135:1242–1256.
87. 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.
88. Hamm M, Bailey R, Shaw G, et al. Physiologically relevant factors influence tau phosphorylation by leucine-rich repeat kinase 2. J Neurosci Res. 2015;93:1567–1580.
89. Shanley MR, Hawley D, Leung S, et al. LRRK2 facilitates tau phosphorylation through strong interaction with tau and cdk5. Biochemistry. 2015;54:5198–5208.
90. Guerreiro PS, Gerhardt E, Lopes Da Fonseca T, et al. LRRK2 promotes tau accumulation, aggregation and release. Mol Neurobiol. 2016;53:3124–3135.
91. Krumova P, Reyniers L, Meyer M, et al. Chemical genetic approach identifies microtubule affinity-regulating kinase 1 as a leucine-rich repeat kinase 2 substrate. Faseb J. 2015;29:2980–2992.
92. 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.
93. Russo I, Berti G, Plotegher N, et al. Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-kappaB p50 signaling in cultured microglia cells. J Neuroinflammation. 2015;12:230.
94. Gardet A, Benita Y, Li C, et al. LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol. 2010;185:5577–5585.
95. Kuss M, Adamopoulou E, Kahle PJ. Interferon-gamma induces leucine-rich repeat kinase LRRK2 via extracellular signal-regulated kinase ERK5 in macrophages. J Neurochem. 2014;129:980–987.
96. Moehle MS, Daher JP, Hull TD, et al. The G2019S LRRK2 mutation increases myeloid cell chemotactic responses and enhances LRRK2 binding to actin-regulatory proteins. Hum Mol Genet. 2015;24:4250–4267.
97. Dzamko N, Inesta-Vaquera F, Zhang J, et al. The kappaB kinase family phosphorylates the Parkinson’s disease kinase LRRK2 at Ser935 and Ser910 during toll-like receptor signaling. Plos One. 2012;7:e39132.
98. 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. 2012;208:41–48.
99. Moehle MS, Webber PJ, Tse T, et al. LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci. 2012;32:1602–1611.
100. Brockmann K, Apel A, Schulte C, et al. Inflammatory profile in LRRK2-associated prodromal and clinical PD. J Neuroinflammation. 2016;13:122.• An interesting report comparing prodromal and clinical PD, which also shows the widening scope of current LRRK2 research.
101. 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.
102. Luerman GC, Nguyen C, Samaroo H, et al. Phosphoproteomic evaluation of pharmacological inhibition of leucine-rich repeat kinase 2 reveals significant off-target effects of LRRK-2-IN-1. J Neurochem. 2014;128:561–576.•• Inhibitors are widely used in current research; this increases awareness about drugs’ off-target effects. This is highlighted as LRRK2-IN-1 was a commonly employed LRRK2 inhibitor until its off-target effects were reported.
103. 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;16:223–232.
104. Jankovic J. Motor fluctuations and dyskinesias in Parkinson’s disease:clinical manifestations. Mov Disord. 2005;20(Suppl 11):S11–6.
105. Muller T, Russ H. Levodopa, motor fluctuations and dyskinesia in Parkinson’s disease. Expert Opin Pharmacother. 2006;7:1715–1730.