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Role of LRRK2 kinase dysfunction in Parkinson disease

  • Azad Kumar (a1) and Mark R. Cookson (a1)

Parkinson disease is a common and usually sporadic neurodegenerative disorder. However, a subset of cases are inherited and, of these, mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of disease. Here, we will discuss recent progress in understanding how LRRK2 mutations lead to disease and how this might have therapeutic implications. The effect of mutations on LRRK2 enzyme function provides clues as to which functions of the protein are important to disease. Recent work has focused on the kinase and GTP-binding domains of LRRK2, and it is assumed that these will be therapeutically important, although there is a substantial amount of work to be done to address this hypothesis.

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*Corresponding author: Mark R. Cookson, Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707, USA. E-mail:
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1 M.R. Cookson (2005) The biochemistry of Parkinson's disease. Annual Reviews of Biochemistry 74, 29-52

2 M.R. Cookson and O. Bandmann (2010) Parkinson's disease: insights from pathways. Human Molecular Genetics 19, R21-R27

3 J. Hardy (2010) Genetic analysis of pathways to Parkinson disease. Neuron 68, 201-206

5 J.M. Taymans and M.R. Cookson (2010) Mechanisms in dominant parkinsonism: the toxic triangle of LRRK2, alpha-synuclein, and tau. Bioessays 32, 227-235

6 G. Manning (2002) The protein kinase complement of the human genome. Science 298, 1912-1934

7 I. Marin , W.N. van Egmond and P.J. van Haastert (2008) The Roco protein family: a functional perspective. FASEB Journal 22, 3103-3110

8 K. Gotthardt (2008) Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase. EMBO Journal 27, 2239-2249

9 Z. Berger , K.A. Smith and M.J. Lavoie (2010) Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry 49, 5511-5523

10 N. Dzamko (2010) Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14–3–3 binding and altered cytoplasmic localization. Biochemical Journal 430, 405-413

11 B.I. Giasson (2006) Biochemical and pathological characterization of Lrrk2. Annals of Neurology 59, 315-322

12 E. Greggio (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiology of Disease 23, 329-341

13 R.J. Nichols (2010) 14–3–3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochemical Journal 430, 393-404

14 A.B. West (2005) Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proceedings of the National Academy of Sciences of the United States of America 102, 16842-16847

15 J. Deng (2008) Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proceedings of the National Academy of Sciences of the United States of America 105, 1499-1504

16 L. Guo (2007) The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Experimental Cell Research 313, 3658-3670

17 P.A. Lewis (2007) The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochemical and Biophysical Research Communications 357, 668-671

19 G. Ito (2007) GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. Biochemistry 46, 1380-1388

20 M. Liu (2010) Kinetic mechanistic studies of wild-type leucine-rich repeat kinase 2: characterization of the kinase and GTPase activities. Biochemistry 49, 2008-2017

21 C.J. Gloeckner (2010) Phosphopeptide analysis reveals two discrete clusters of phosphorylation in the N-terminus and the Roc domain of the Parkinson-disease associated protein kinase LRRK2. Journal of Proteome Research 9, 1738-1745

22 E. Greggio (2009) The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites. Biochemical and Biophysical Research Communications 389, 449-454

23 S. Kamikawaji , G. Ito and T. Iwatsubo (2009) Identification of the autophosphorylation sites of LRRK2. Biochemistry 48, 10963-10975

24 P.P. Pungaliya (2010) Identification and characterization of a leucine-rich repeat kinase 2 (LRRK2) consensus phosphorylation motif. PLoS One 5, e13672

25 E. Greggio (2008) The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. Journal of Biological Chemistry 283, 16906-16914

26 N.D. Jorgensen (2009) The WD40 domain is required for LRRK2 neurotoxicity. PLoS One 4, e8463

27 C.L. Klein (2009) Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment. Journal of Neurochemistry 111, 703-715

28 H.S. Ko (2009) CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proceedings of the National Academy of Sciences of the United States of America 106, 2897-2902

29 B. Lu (2010) Expression, purification and preliminary biochemical studies of the N-terminal domain of leucine-rich repeat kinase 2. Biochimica et Biophysica Acta 1804, 1780-1784

30 S. Sen , P.J. Webber and A.B. West (2009) Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. Journal of Biological Chemistry 284, 36346-36356

31 J. Alegre-Abarrategui (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Human Molecular Genetics 18, 4022-4034

32 T. Hatano (2007) Leucine-rich repeat kinase 2 associates with lipid rafts. Human Molecular Genetics 16, 678-690

33 J. Miklossy (2006) LRRK2 expression in normal and pathologic human brain and in human cell lines. Journal of Neuropathology and Experimental Neurology 65, 953-963

34 S. Biskup (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Annals of Neurology 60, 557-569

35 S. Higashi (2009) Abnormal localization of leucine-rich repeat kinase 2 to the endosomal-lysosomal compartment in lewy body disease. Journal of Neuropathology and Experimental Neurology 68, 994-1005

36 M. Funayama (2002) A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2–q13.1. Annals of Neurology 51, 296-301

37 C. Paisan-Ruiz (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600

38 A. Zimprich (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607

39 M. Funayama (2005) An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Annals of Neurology 57, 918-921

40 W.P. Gilks (2005) A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365, 415-416

41 S. Goldwurm (2005) The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor. Journal of Medical Genetics 42, e65

42 J. Infante (2006) LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease. Neuroscience Letters 395, 224-226

43 J. Kachergus (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. American Journal of Human Genetics 76, 672-680

44 S. Lesage (2006) LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. New England Journal of Medicine 354, 422-423

45 S. Lesage (2005) G2019S LRRK2 mutation in French and North African families with Parkinson's disease. Annals of Neurology 58, 784-787

46 S. Lesage (2005) LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century. American Journal of Human Genetics 77, 330-332

47 L.J. Ozelius (2006) LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. New England Journal of Medicine 354, 424-425

48 A. Rajput (2006) Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 67, 1506-1508

49 U. Kumari and E.K. Tan (2009) LRRK2 in Parkinson's disease: genetic and clinical studies from patients. FEBS Journal 276, 6455-6463

51 V. Daniels (2011) Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant. Journal of Neurochemistry 116, 304-315

52 A.B. West (2007) Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Human Molecular Genetics 16, 223-232

53 K. Haugarvoll and Z.K. Wszolek (2009) Clinical features of LRRK2 parkinsonism. Parkinsonism and Related Disorders 15 (Suppl 3), S205-S208

54 R.N. Alcalay (2010) Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study. Archives of Neurology 67, 1116-1122

55 D.S. Goldstein (2007) Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation. Neurology 69, 1580-1584

56 C. Wider , D.W. Dickson and Z.K. Wszolek (2010) Leucine-rich repeat kinase 2 gene-associated disease: redefining genotype-phenotype correlation. Neurodegenerative Diseases 7, 175-179

58 D.M. Kay (2005) Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Movement Disorders 20, 1077-1078

59 J.C. Dachsel and M.J. Farrer (2010) LRRK2 and Parkinson disease. Archives of Neurology 67, 542-547

60 L.N. Clark (2006) Frequency of LRRK2 mutations in early- and late-onset Parkinson disease. Neurology 67, 1786-1791

61 J. Ruiz-Martinez (2010) Penetrance in Parkinson's disease related to the LRRK2 R1441G mutation in the Basque country (Spain). Movement Disorders 25, 2340-2345

62 S. Gehrke (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466, 637-641

63 Y. Imai (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO Journal 27, 2432-2443

64 T. Kanao (2010) Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila. Human Molecular Genetics 19, 3747-3758

65 S. Lee (2010) LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction. Journal of Neuroscience 30, 16959-16969

66 S.B. Lee (2007) Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochemical and Biophysical Research Communications 358, 534-539

67 C.H. Lin (2010) LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3ss. Journal of Neuroscience 30, 13138-13149

68 Z. Liu (2008) A Drosophila model for LRRK2-linked parkinsonism. Proceedings of the National Academy of Sciences of the United States of America 105, 2693-2698

69 C.H. Ng (2009) Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. Journal of Neuroscience 29, 11257-11262

70 L.S. Tain (2009) Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nature Neuroscience 12, 1129-1135

71 K. Venderova (2009) Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease. Human Molecular Genetics 18, 4390-4404

72 C.H. Hsu (2010) MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2. Journal of Neurochemistry 112, 1593-1604

73 S. Saha (2009) LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. Journal of Neuroscience 29, 9210-9218

74 A. Sakaguchi-Nakashima (2007) LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Current Biology 17, 592-598

75 J. Samann (2009) Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. Journal of Biological Chemistry 284, 16482-16491

76 C. Yao (2010) LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease. Neurobiology of Disease 40, 73-81

77 D. Wang (2008) Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons. Molecular Neurodegeneration 3, 3

78 I. Marin (2008) Ancient origin of the Parkinson disease gene LRRK2. Journal of Molecular Evolution 67, 41-50

79 E. Andres-Mateos (2009) Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Journal of Neuroscience 29, 15846-15850

80 X. Lin (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64, 807-827

81 Y. Tong (2010) Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proceedings of the National Academy of Sciences of the United States of America 107, 9879-9884

82 Y. Tong (2009) R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proceedings of the National Academy of Sciences of the United States of America 106, 14622-14627

83 X. Li (2010) Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson's disease mutation G2019S. Journal of Neuroscience 30, 1788-1797

84 Y. Li (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nature Neuroscience 12, 826-828

85 H.L. Melrose (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiology of Disease 40, 503-517

86 B. Winner (2011) Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiology of Disease 41, 706-716

87 B.D. Lee (2010) Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nature Medicine 16, 998-1000

88 J. Dusonchet (2011) A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2. Journal of Neuroscience 31, 907-912

89 J.C. Dachsel (2010) A comparative study of Lrrk2 function in primary neuronal cultures. Parkinsonism and Related Disorders 16, 650-655

90 D. MacLeod (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52, 587-593

91 L. Parisiadou (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. Journal of Neuroscience 29, 13971-13980

92 K. Nuytemans (2010) Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Human Mutation 31, 763-780

93 W. Satake (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nature Genetics 41, 1303-1307

94 J. Simon-Sanchez (2009) Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nature Genetics 41, 1308-1312

95 W.W. Smith (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nature Neuroscience 9, 1231-1233

96 M. Liu (2010) Development of a mechanism-based high-throughput screen assay for leucine-rich repeat kinase 2 – discovery of LRRK2 inhibitors. Analytical Biochemistry 404, 186-192

97 R.J. Nichols (2009) Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease. Biochemical Journal 424, 47-60

98 L.J. Reichling and S.M. Riddle (2009) Leucine-rich repeat kinase 2 mutants I2020T and G2019S exhibit altered kinase inhibitor sensitivity. Biochemical and Biophysical Research Communications 384, 255-258

99 X. Deng (2011) Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nature Chemical Biology 7, 203–25

M.R. Cookson (2010). The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nature Reviews Neuroscience 11, 791-797

E. Greggio and M.R. Cookson (2009) Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro 1, e0002

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