Browse > Article
http://dx.doi.org/10.5483/BMBRep.2015.48.5.032

Function and dysfunction of leucine-rich repeat kinase 2 (LRRK2): Parkinson's disease and beyond  

Bae, Jae Ryul (Department of Neuroscience, Kyung Hee University)
Lee, Byoung Dae (Department of Neuroscience, Kyung Hee University)
Publication Information
BMB Reports / v.48, no.5, 2015 , pp. 243-248 More about this Journal
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). As such, functions and dysfunctions of LRRK2 in PD have been the subject of extensive investigation. In addition to PD, increasing evidence is suggesting that LRRK2 is associated with a wide range of diseases. Genome-wide association studies have implicated LRRK2 in Crohn's disease (CD) and leprosy, and the carriers with pathogenic mutations of LRRK2 show increased risk to develop particular types of cancer. LRRK2 mutations are rarely found in Alzheimer's disease (AD), but LRRK2 might play a part in tauopathies. The association of LRRK2 with the pathogenesis of apparently unrelated diseases remains enigmatic, but it might be related to the yet unknown diverse functions of LRRK2. Here, we reviewed current knowledge on the link between LRRK2 and several diseases, including PD, AD, CD, leprosy, and cancer, and discussed the possibility of targeting LRRK2 in such diseases. [BMB Reports 2015; 48(5): 243-248]
Keywords
Leucine rich repeat kinase 2 (LRRK2); Parkinson's disease (PD); Alzheimer's disease (AD); Crohn's disease(CD);
Citations & Related Records
연도 인용수 순위
  • Reference
1 Paisan-Ruiz C, Jain S, Evans EW et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600   DOI   ScienceOn
2 Zimprich A, Biskup S, Leitner P et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607   DOI   ScienceOn
3 Bialik S and Kimchi A (2010) Lethal weapons: DAP-kinase, autophagy and cell death: DAP-kinase regulates autophagy. Curr Opin Cell Biol 22, 199-205   DOI   ScienceOn
4 Kuo JC, Wang WJ, Yao CC, Wu PR and Chen RH (2006) The tumor suppressor DAPK inhibits cell motility by blocking the integrin-mediated polarity pathway. J Cell Biol 172, 619-631   DOI   ScienceOn
5 Wang LH, Besirli CG and Johnson EM Jr (2004) Mixedlineage kinases: a target for the prevention of neurodegeneration. Annu Rev Pharmacol Toxicol 44, 451-474   DOI   ScienceOn
6 Chuang YT, Fang LW, Lin-Feng MH, Chen RH and Lai MZ (2008) The tumor suppressor death-associated protein kinase targets to TCR-stimulated NF-kappa B activation. J Immunol 180, 3238-3249   DOI
7 Chuang YT, Lin YC, Lin KH et al (2011) Tumor suppressor death-associated protein kinase is required for full IL-1beta production. Blood 117, 960-970   DOI   ScienceOn
8 Bialik S and Kimchi A (2006) The death-associated protein kinases: structure, function, and beyond. Annu Rev Biochem 75, 189-210   DOI   ScienceOn
9 Ferrer I, Blanco R, Carmona M et al (2001) Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson's disease and Dementia with Lewy bodies. J Neural Transm 108, 1383-1396   DOI   ScienceOn
10 Parkinson Study G (2004) The safety and tolerability of a mixed lineage kinase inhibitor (CEP-1347) in PD. Neurology 62, 330-332   DOI   ScienceOn
11 Zhang D, Lin J and Han J (2010) Receptor-interacting protein (RIP) kinase family. Cell Mol Immunol 7, 243-249   DOI   ScienceOn
12 Meylan E and Tschopp J (2005) The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci 30, 151-159   DOI   ScienceOn
13 Dzamko N, Inesta-Vaquera F, Zhang J et al (2012) The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-like receptor signaling. PLoS One 7, e39132   DOI
14 Gardet A, Benita Y, Li C et al (2010) LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol 185, 5577-5585   DOI
15 Tong Y, Yamaguchi H, Giaime E et al (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. Proc Natl Acad Sci U S A 107, 9879-9884   DOI   ScienceOn
16 Tong Y, Giaime E, Yamaguchi H et al (2012) Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol Neurodegener 7, 2   DOI   ScienceOn
17 Lee S, Liu HP, Lin WY, Guo H and Lu B (2010) LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction. J Neurosci 30, 16959-16969   DOI   ScienceOn
18 Parisiadou L, Yu J, Sgobio C et al (2014) LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity. Nat Neurosci 17, 367-376   DOI   ScienceOn
19 Herzig MC, Kolly C, Persohn E et al (2011) LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum Mol Genet 20, 4209-4223   DOI   ScienceOn
20 Thevenet J, Pescini Gobert R, Hooft van Huijsduijnen R, Wiessner C and Sagot YJ (2011) Regulation of LRRK2 expression points to a functional role in human monocyte maturation. PLoS One 6, e21519   DOI
21 Hakimi M, Selvanantham T, Swinton E et al (2011) Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm 118, 795-808   DOI   ScienceOn
22 Funayama M, Hasegawa K, Ohta E et al (2005) An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol 57, 918-921   DOI   ScienceOn
23 Alegre-Abarrategui J, Christian H, Lufino MM et al (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 18, 4022-4034   DOI   ScienceOn
24 Liu Z, Wang X, Yu Y et al (2008) A Drosophila model for LRRK2-linked parkinsonism. Proc Natl Acad Sci U S A 105, 2693-2698   DOI   ScienceOn
25 Matta S, Van Kolen K, da Cunha R et al (2012) LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 75, 1008-1021   DOI   ScienceOn
26 Tong Y, Pisani A, Martella G et al (2009) R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proc Natl Acad Sci U S A 106, 14622-14627   DOI   ScienceOn
27 Chen CY, Weng YH, Chien KY et al (2012) (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell Death Differ 19, 1623-1633   DOI   ScienceOn
28 Martin I, Kim JW, Lee BD et al (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157, 472-485   DOI   ScienceOn
29 MacLeod D, Dowman J, Hammond R, Leete T, Inoue K and Abeliovich A (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52, 587-593   DOI   ScienceOn
30 Hockey LN, Kilpatrick BS, Eden ER et al (2015) Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition. J Cell Sci 128, 232-238   DOI   ScienceOn
31 Dodson MW, Zhang T, Jiang C, Chen S and Guo M (2012) Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning. Hum Mol Genet 21, 1350-1363   DOI
32 Kim S, Seo JH and Suh YH (2004) Alpha-synuclein, Parkinson's disease, and Alzheimer's disease. Parkinsonism Relat Disord 10 Suppl 1, S9-13   DOI   ScienceOn
33 Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I et al (2012) Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol Med 4, 380-395   DOI
34 Koehler NK, Stransky E, Shing M et al (2013) Altered serum IgG levels to alpha-synuclein in dementia with Lewy bodies and Alzheimer's disease. PLoS One 8, e64649   DOI
35 Guo JL, Covell DJ, Daniels JP et al (2013) Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell 154, 103-117   DOI   ScienceOn
36 Culvenor JG, McLean CA, Cutt S et al (1999) Non-Abeta component of Alzheimer's disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Abeta amyloid. Am J Pathol 155, 1173-1181   DOI   ScienceOn
37 Linnertz C, Lutz MW, Ervin JF et al (2014) The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease. Hum Mol Genet 23, 4814-4821   DOI   ScienceOn
38 Lin X, Parisiadou L, Gu XL et al (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64, 807-827   DOI   ScienceOn
39 Kawakami F, Yabata T, Ohta E et al (2012) 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   DOI
40 Li Y, Liu W, Oo TF et al (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci 12, 826-828   DOI   ScienceOn
41 Franchi L, Warner N, Viani K and Nunez G (2009) Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev 227, 106-128   DOI   ScienceOn
42 Moskvina V, Harold D, Russo G et al (2013) Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk. JAMA Neurol 70, 1268-1276
43 Fuss IJ, Neurath M, Boirivant M et al (1996) Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 157, 1261-1270
44 Barrett JC, Hansoul S, Nicolae DL et al (2008) Genomewide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40, 955-962   DOI   ScienceOn
45 Zhang FR, Huang W, Chen SM et al (2009) Genomewide association study of leprosy. N Engl J Med 361, 2609-2618   DOI   ScienceOn
46 Xavier RJ and Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427-434   DOI   ScienceOn
47 Niessner M and Volk BA (1995) Altered Th1/Th2 cytokine profiles in the ntestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction (RT-PCR). Clin Exp Immunol 101, 428-435   DOI
48 Liu Z, Lee J, Krummey S, Lu W, Cai H and Lenardo MJ (2011) The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol 12, 1063-1070   DOI   ScienceOn
49 Krutzik SR, Ochoa MT, Sieling PA et al (2003) Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat Med 9, 525-532   DOI   ScienceOn
50 Devine MJ, Plun-Favreau H and Wood NW (2011) Parkinson's disease and cancer: two wars, one front. Nat Rev Cancer 11, 812-823   DOI   ScienceOn
51 Looyenga BD, Furge KA, Dykema KJ et al (2011) Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas. Proc Natl Acad Sci U S A 108, 1439-1444   DOI   ScienceOn
52 Agalliu I, San Luciano M, Mirelman A et al (2015) Higher Frequency of Certain Cancers in LRRK2 G2019S Mutation Carriers With Parkinson Disease: A Pooled Analysis. JAMA Neurol 72, 58-65   DOI   ScienceOn
53 Inzelberg R, Cohen OS, Aharon-Peretz J et al (2012) The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers. Neurology 78, 781-786   DOI
54 Saunders-Pullman R, Barrett MJ, Stanley KM et al (2010) LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease. Mov Disord 25, 2536-2541   DOI   ScienceOn
55 Kuo JC, Lin JR, Staddon JM, Hosoya H and Chen RH (2003) Uncoordinated regulation of stress fibers and focal adhesions by DAP kinase. J Cell Sci 116, 4777-4790   DOI   ScienceOn
56 Gingras AC, Raught B and Sonenberg N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68, 913-963   DOI   ScienceOn
57 Gehrke S, Imai Y, Sokol N and Lu B (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466, 637-641   DOI   ScienceOn