Function and dysfunction of leucine-rich repeat kinase 2 (LRRK2): Parkinson’s disease and beyond
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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.
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.
참고문헌 (57)
- Paisan-Ruiz C, "Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease", Neuron, 44, pp.595~600 (2004)
- Zimprich A, "Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology", Neuron, 44, pp.601~607 (2004)
- Bialik S, "Lethal weapons: DAP-kinase, autophagy and cell death: DAP-kinase regulates autophagy", Curr Opin Cell Biol, 22, pp.199~205 (2010)
- Kuo JC, "The tumor suppressor DAPK inhibits cell motility by blocking the integrin-mediated polarity pathway", J Cell Biol, 172, pp.619~631 (2006)
- Kuo JC, "Uncoordinated regulation of stress fibers and focal adhesions by DAP kinase", J Cell Sci, 116, pp.4777~4790 (2003)
- Chuang YT, "The tumor suppressor death-associated protein kinase targets to TCR-stimulated NF-kappa B activation", J Immunol, 180, pp.3238~3249 (2008)
- Chuang YT, "Tumor suppressor death-associated protein kinase is required for full IL-1beta production", Blood, 117, pp.960~970 (2011)
- Bialik S, "The death-associated protein kinases: structure, function, and beyond", Annu Rev Biochem, 75, pp.189~210 (2006)
- Wang LH, "Mixedlineage kinases: a target for the prevention of neurodegeneration", Annu Rev Pharmacol Toxicol, 44, pp.451~474 (2004)
- Ferrer I, "Active, phosphorylation-dependent mitogen-activated protein kinase(MAPK", ERK), stress-activated protein kinase, JNK), and p38 kinase expression in Parkinson's disease and Dementia with Lewy bodies, pp.J Neural Transm, 2001[DOI]
- Parkinson Study G, "The safety and tolerability of a mixed lineage kinase inhibitor (CEP-1347) in PD", Neurology, 62, pp.330~332 (2004)
- Zhang D, "Receptor-interacting protein(RIP)kinase family", Cell Mol Immunol, 7, pp.243~249 (2010)
- Meylan E, "The RIP kinases: crucial integrators of cellular stress", Trends Biochem Sci, 30, pp.151~159 (2005)
- Dzamko N, "The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-like receptor signaling", PLoS One, 7, pp.e39132~ (2012)
- Gardet A, "LRRK2 is involved in the IFN-gamma response and host response to pathogens", J Immunol, 185, pp.5577~5585 (2010)
- Lee S, "LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction", J Neurosci, 30, pp.16959~16969 (2010)
- Parisiadou L, "LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity", Nat Neurosci, 17, pp.367~376 (2014)
- Tong Y, "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, pp.9879~9884 (2010)
- Tong Y, "Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway", Mol Neurodegener, 7, pp.2~ (2012)
- Herzig MC, "LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice", Hum Mol Genet, 20, pp.4209~4223 (2011)
- Thevenet J, "Regulation of LRRK2 expression points to a functional role in human monocyte maturation", PLoS One, 6, pp.e21519~ (2011)
- Hakimi M, "Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures", J Neural Transm, 118, pp.795~808 (2011)
- Funayama M, "An LRRK2mutation as a cause for the parkinsonism in the original PARK8 family", Ann Neurol, 57, pp.918~921 (2005)
- Liu Z, "A Drosophila model for LRRK2-linked parkinsonism", Proc Natl Acad Sci U S A, 105, pp.2693~2698 (2008)
- Tong Y, "R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice", Proc Natl Acad Sci U S A, 106, pp.14622~14627 (2009)
- Alegre-Abarrategui J, "LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model", Hum Mol Genet, 18, pp.4022~4034 (2009)
- Chen CY, "LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD", Cell Death Differ, 19, pp.1623~1633 (2012)
- Matta S, "LRRK2controls an EndoA phosphorylation cycle in synaptic endocytosis", Neuron, 75, pp.1008~1021 (2012)
- Martin I, "Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease", Cell, 157, pp.472~485 (2014)
- MacLeod D, "The familial Parkinsonism gene LRRK2 regulates neurite process morphology", Neuron, 52, pp.587~593 (2006)
- Hockey LN, "Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition", J Cell Sci, 128, pp.232~238 (2015)
- Dodson MW, "Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning", Hum Mol Genet, 21, pp.1350~1363 (2012)
- Sanchez-Danes A, "Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease", EMBO Mol Med, 4, pp.380~395 (2012)
- Guo JL, "Distinct alpha-synuclein strains differentially promote tau inclusions in neurons", Cell, 154, pp.103~117 (2013)
- Kim S, "Alpha-synuclein, Parkinson's disease, and Alzheimer's disease", Parkinsonism Relat Disord, 10(1), pp.9~13 (2004)
- Culvenor JG, "Non-Abeta component of Alzheimer's disease amyloid(NAC)revisited. NAC and alpha-synuclein are not associated with Abeta amyloid", Am J Pathol, 155, pp.1173~1181 (1999)
- Koehler NK, "Altered serum IgG levels to alpha-synuclein in dementia with Lewy bodies and Alzheimer's disease", PLoS One, 8, pp.e64649~ (2013)
- Linnertz C, "The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease", Hum Mol Genet, 23, pp.4814~4821 (2014)
- Lin X, "Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein", Neuron, 64, pp.807~827 (2009)
- Kawakami F, "LRRK2 phosphorylates tubulin-associated tau but not the free molecule:LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth", PLoS One, 7, pp.e30834~ (2012)
- Li Y, "Mutant LRRK2(R1441G)BAC transgenic mice recapitulate cardinal features of Parkinson's disease", Nat Neurosci, 12, pp.826~828
- Moskvina V, "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, pp.1268~1276 (2013)
- Barrett JC, "Genomewide association defines more than 30 distinct susceptibility loci for Crohn's disease", Nat Genet, 40, pp.955~962 (2008)
- Zhang FR, "Genomewide association study of leprosy", N Engl J Med, 361, pp.2609~2618 (2009)
- Xavier RJ, "Unravelling the pathogenesis of inflammatory bowel disease", Nature, 448, pp.427~434 (2007)
- Fuss IJ, "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, pp.1261~1270 (1996)
- Niessner M, "Altered Th1", Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction(RT-PCR), 1995, pp.101, 428~435
- Liu Z, "The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease", Nat Immunol, 12, pp.1063~1070 (2011)
- Franchi L, "Function of Nod-like receptors in microbial recognition and host defense", Immunol Rev, 227, pp.106~128 (2009)
- Krutzik SR, "Activation and regulation of Toll-like receptors 2 and 1 in human leprosy", Nat Med, 9, pp.525~532 (2003)
- Devine MJ, "Parkinson's disease and cancer: two wars, one front", Nat Rev Cancer, 11, pp.812~823 (2011)
- Agalliu I, "Higher Frequency of Certain Cancers in LRRK2 G2019S Mutation Carriers With Parkinson Disease: A Pooled Analysis", JAMA Neurol, 72, pp.58~65 (2015)
- Inzelberg R, "The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers", Neurology, 78, pp.781~786 (2012)
- Saunders-Pullman R, "LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease", Mov Disord, 25, pp.2536~2541 (2010)
- Looyenga BD, "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, pp.1439~1444 (2011)
- Gehrke S, "Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression", Nature, 466, pp.637~641 (2010)
- Gingras AC, "eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation", Annu Rev Biochem, 68, pp.913~963 (1999)
