Rab GTPases as Physiological Substrates of LRRK2 Kinase

다국어 초록 (Multilingual Abstract)

LRRK2 (Leucine-Rich Repeat Kinase 2) is a gene whose specific mutations cause Parkinson’s disease (PD), the most common neurodegenerative movement disorder. LRRK2 harbors GTPase and kinase activities, two enzyme activities that play critical roles in the regulation of cellular signal transduction. Among the several LRRK2 pathogenic mutations, the most prevalent G2019S mutation increases its kinase activity when compared with the wild-type (WT), suggesting that LRRK2 kinase substrates are potential culprits of PD pathogenesis. Although there were several studies to identify LRRK2 kinase substrates, most of them mainly employed in vitro kinase assays. Therefore, it remains uncertain whether the identified substrates were real physiological substrates. However, efforts to determine physiological LRRK2 kinase substrates have recently identified several members of the Rab GTPase family as physiological LRRK2 kinase substrates. A conserved threonine or serine in the switch II domain of certain Rab GTPase family members (Rab3A/B/C/D, Rab5A/B, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) has been pinpointed to be phosphorylated by LRRK2 in cells using sophisticated phosphoproteomics technology in combination with LRRK2-specific kinase inhibitors. The Rab GTPases regulate vesicle trafficking, suggesting that LRRK2 may be a regulator of such vesicle trafficking, confirming previously suggested LRRK2 functions. However, how the consequence of the LRRK2-mediated Rab phosphorylation is related to PD pathogenesis is not clear. This review briefly summarizes the recent results about LRRK2-mediated Rab phosphorylation studies.

참고문헌 (Reference)

• 1 Scott D, "α-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis" 32 : 10129-10135, 2012
• 2 Clayton DF, "The synucleins : a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease" 21 : 249-254, 1998
• 3 Li JQ, "The role of the LRRK2 gene in parkinsonism" 9 : 47-, 2014
• 4 Larsen SB, "The genetic architecture of mitochondrial dysfunction in Parkinson’s disease" 373 : 21-37, 2018
• 5 Gao Y, "The emerging role of Rab GTPases in the pathogenesis of Parkinson’s disease" 33 : 196-207, 2018
• 6 Sveinbjornsdottir S, "The clinical symptoms of Parkinson’s disease" 139 (139): 318-324, 2016
• 7 Marín I, "The Roco protein family : a functional perspective" 22 : 3103-3110, 2008
• 8 Mir R, "The Parkinson’s disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human" 475 : 1861-1883, 2018
• 9 Manzoni C, "The LRRK2-macroautophagy axis and its relevance to Parkinson’s disease" 45 : 155-162, 2017
• 10 Price A, "The LRRK2 signalling system" 373 : 39-50, 2018
• 11 Carrion MD, "The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions" 7 : 5377-, 2017
• 12 Lu CS, "The LRRK2 Arg1628Pro variant is a risk factor for Parkinson’s disease in the Chinese population" 9 : 271-276, 2008
• 13 Rivero-Ríos P, "The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A" 2019
• 14 Chan SL, "Targeting LRRK2 in Parkinson’s disease : an update on recent developments" 21 : 601-610, 2017
• 15 Steger M, "Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis" 6 : e31012-, 2017
• 16 Esposito G, "Synaptic vesicle trafficking and Parkinson’s disease" 72 : 134-144, 2012
• 17 Dodson MW, "Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning" 21 : 1350-1363, 2012
• 18 Plowey ED, "Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells" 105 : 1048-1056, 2008
• 19 Martin I, "Ribosomal protein s15 phosphorylation mediates LRRK2neurodegeneration in Parkinson’s disease" 157 : 472-485, 2014
• 20 Kim KS, "Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2complex stabilization is altered in Parkinson’s disease" 115 : E5164-E5173, 2018
• 21 Thévenet J, "Regulation of LRRK2 expression points to a functional role in human monocyte maturation" 6 : e21519-, 2011
• 22 Tang BL, "Rabs, membrane dynamics, and Parkinson’s disease" 232 : 1626-1633, 2017
• 23 Purlyte E, "Rab29activation of the Parkinson’s disease-associated LRRK2 kinase" 37 : 1-18, 2018
• 24 Stenmark H, "Rab GTPases as coordinators of vesicle traffic" 10 : 513-525, 2009
• 25 Kiral FR, "Rab GTPases and membrane trafficking in neurodegeneration" 28 : R471-R486, 2018
• 26 Shi MM, "Rab GTPases : the key players in the molecular pathway of Parkinson’s disease" 11 : 81-, 2017
• 27 Khaligh A, "RAB7L1 promoter polymorphism and risk of Parkinson’s disease; a case-control study" 39 : 468-471, 2017
• 28 MacLeod DA, "RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk" 77 : 425-439, 2013
• 29 Araki M, "Physiological and pathological functions of LRRK2: implications from substrate proteins" 2 : NS20180005-, 2018
• 30 Li X, "Phosphorylation-dependent 14-3-3 binding to LRRK2 is impaired by common mutations of familial Parkinson’s disease" 6 : e17153-, 2011
• 31 Ho DH, "Phosphorylation of p53 by LRRK2 induces microglial tumor necrosis factor α-mediated neurotoxicity" 482 : 1088-1094, 2017
• 32 Parisiadou L, "Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis" 29 : 13971-13980, 2009
• 33 Trancikova A, "Phosphorylation of 4E-BP1 in the mammalian brain is not altered by LRRK2 expression or pathogenic mutations" 7 : e47784-, 2012
• 34 Imai Y, "Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila" 27 : 2432-2443, 2008
• 35 Steger M, "Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases" 5 : e12813-, 2016
• 36 Healy DG, "Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease : a casecontrol study" 7 : 583-590, 2008
• 37 Gehrke S, "Pathogenic LRRK2negatively regulates microRNA-mediated translational repression" 466 : 637-641, 2010
• 38 Fujimoto T, "Parkinson’s disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology" 495 : 1708-1715, 2018
• 39 Madero-Pérez J, "Parkinson disease-associated mutations in LRRK2cause centrosomal defects via Rab8a phosphorylation" 13 : 3-, 2018
• 40 Kalogeropulou AF, "P62/SQSTM1 is a novel leucine-rich repeat kinase 2(LRRK2)substrate that enhances neuronal toxicity" 475 : 1271-1293, 2018
• 41 Cui H, "Oxidative stress, mitochondrial dysfunction, and aging" 2012 : 646354-, 2012
• 42 Daher JP, "Neurodegenerative phenotypes in an A53T α-synuclein transgenic mouse model are independent of LRRK2" 21 : 2420-2431, 2012
• 43 Wilson GR, "Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology" 95 : 729-735, 2014
• 44 Zimprich A, "Mutations in LRRK2 cause autosomaldominant parkinsonism with pleomorphic pathology" 44 : 601-607, 2004
• 45 Polymeropoulos MH, "Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease" 276 : 2045-2047, 1997
• 46 Hauser DN, "Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism" 51 : 35-42, 2013
• 47 Anderson CA, "Meta-analysis identifies 29additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47" 43 : 246-252, 2011
• 48 Cookson MR, "Mechanisms of mutant LRRK2 neurodegeneration" 14 : 227-239, 2017
• 49 Qing H, "Lrrk2phosphorylates alpha synuclein at serine 129 : Parkinson disease implications" 387 : 149-152, 2009
• 50 Mata IF, "Lrrk2 pathogenic substitutions in Parkinson’s disease" 6 : 171-177, 2005
• 51 Biskup S, "Localization of LRRK2 to membranous and vesicular structures in mammalian brain" 60 : 557-569, 2006
• 52 Lin X, "Leucinerich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant alphasynuclein" 64 : 807-827, 2009
• 53 Monfrini E, "Leucine-rich repeat kinase(LRRK2)genetics and Parkinson’s disease" 14 : 3-30, 2017
• 54 Galatsis P, "Leucine-rich repeat kinase 2 inhibitors : a patent review(2014–2016)" 27 : 667-676, 2017
• 55 Piccoli G, "Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain" 34 : 2147-2161, 2014
• 56 Bae EJ, "LRRK2kinase regulates α-synuclein propagation via RAB35 phosphorylation" 9 : 3465-, 2018
• 57 Piccoli G, "LRRK2controls synaptic vesicle storage and mobilization within the recycling pool" 31 : 2225-2237, 2011
• 58 Shin N, "LRRK2 regulates synaptic vesicle endocytosis" 314 : 2055-2065, 2008
• 59 Wang X, "LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1" 21 : 1931-1944, 2012
• 60 Guerreiro PS, "LRRK2 promotes tau accumulation, aggregation and release" 53 : 3124-3135, 2016
• 61 Nichols RJ, "LRRK2 phosphorylation" 14 : 51-70, 2017
• 62 Kawakami F, "LRRK2 phosphorylates tubulin-associated tau but not the free molecule:LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth" 7 : e30834-, 2012
• 63 Liu Z, "LRRK2 phosphorylates membranebound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network" 27 : 385-395, 2018
• 64 윤혜진, "LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25" 생화학분자생물학회 45 (45): 1-11, 2013
• 65 Yu M, "LRRK2 mediated Rab8a phosphorylation promotes lipid storage" 17 : 34-, 2018
• 66 Hinkle KM, "LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor coordination behaviors" 7 : 25-, 2012
• 67 Alessi DR, "LRRK2 kinase in Parkinson’s disease" 360 : 36-37, 2018
• 68 Cirnaru MD, "LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2macro-molecular complex" 7 : 49-, 2014
• 69 Härtlova A, "LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages" 37 : e98694-, 2018
• 70 Guerreiro PS, "LRRK2 interactions with α-synuclein in Parkinson’s disease brains and in cell models" 91 : 513-522, 2013
• 71 Moehle MS, "LRRK2 inhibition attenuates microglial inflammatory responses" 32 : 1602-1611, 2012
• 72 Ho DH, "LRRK2 impairs autophagy by mediating phosphorylation of leucyl-tRNA synthetase" 36 : 431-442, 2018
• 73 Arranz AM, "LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism" 128 : 541-552, 2015
• 74 Yoon JH, "LRRK2 functions as a scaffolding kinase of ASK1-mediated neuronal cell death" 1864 : 2356-2368, 2017
• 75 Shanley MR, "LRRK2 facilitates tau phosphorylation through strong interaction with tau and cdk5" 54 : 5198-5208, 2015
• 76 Ohta E, "LRRK2 directly phosphorylates Akt1 as a possible physiological substrate : impairment of the kinase activity by Parkinson’s diseaseassociated mutations" 585 : 2165-2170, 2011
• 77 Matta S, "LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis" 75 : 1008-1021, 2012
• 78 Gómez-Suaga P, "LRRK2 as a modulator of lysosomal calcium homeostasis with downstream effects on autophagy" 8 : 692-693, 2012
• 79 Rideout HJ, "LRRK2 and the"LRRKtosome"at the crossroads of programmed cell death : clues from RIP kinase relatives" 14 : 193-208, 2017
• 80 Dzamko NL, "LRRK2 and the immune system" 14 : 123-143, 2017
• 81 Singh A, "LRRK2 and mitochondria : recent advances and current views" 1702 : 96-104, 2019
• 82 Eguchi T, "LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis" 115 : E9115-E9124, 2018
• 83 Manzoni C, "LRRK2 and autophagy" 14 : 89-105, 2017
• 84 Pfeffer SR, "LRRK2 and Rab GTPases" 46 : 1707-1712, 2018
• 85 Di Maio R, "LRRK2 activation in idiopathic Parkinson’s disease" 10 : eaar5429-, 2018
• 86 호동환, "LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation" 한국뇌신경과학회 27 (27): 171-180, 2018
• 87 Howlett EH, "LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson’s disease" 26 : 4340-4351, 2017
• 88 Korr D, "LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain" 18 : 910-920, 2006
• 89 Chen ML, "LRRK 2 gene mutations in the pathophysiology of the ROCO domain and therapeutic targets for Parkinson’s disease : a review" 25 : 52-, 2018
• 90 Daher JP, "Interaction of LRRK2 and α-Synuclein in Parkinson’s Disease" 14 : 209-226, 2017
• 91 Kim B, "Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia" 7 : e34693-, 2012
• 92 Islam MS, "Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson’s disease" 25 : 5365-5382, 2016
• 93 Franke A, "Genome-wide meta-analysis increases to 71the number of confirmed Crohn’s disease susceptibility loci" 42 : 1118-1125, 2010
• 94 Farrer MJ, "Genetics of Parkinson disease : paradigm shifts and future prospects" 7 : 306-318, 2006
• 95 Nichols WC, "Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease" 365 : 410-412, 2005
• 96 Nguyen AP, "G2019S LRRK2 enhances the neuronal transmission of tau in the mouse brain" 27 : 120-134, 2018
• 97 김혜정, "Effect of leucine-rich repeat kinase 2 (LRRK2) on protein synthesis" 한국통합생물학회 22 (22): 15-21, 2018
• 98 Jeong GR, "Dysregulated phosphorylation of Rab GTPases by LRRK2 induces neurodegeneration" 13 : 8-, 2018
• 99 Tsika E, "Contribution of GTPase activity to LRRK2-associated Parkinson disease" 4 : 164-170, 2013
• 100 Farrer M, "Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications" 55 : 174-179, 2004
• 101 Zhang Q, "Commensal bacteria direct selective cargo sorting to promote symbiosis" 16 : 918-926, 2015
• 102 Paisán-Ruíz C, "Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease" 44 : 595-600, 2004
• 103 Kestenbaum M, "Clinical features of LRRK2 carriers with Parkinson’s disease" 14 : 31-48, 2017
• 104 Zhen Y, "Cellular functions of Rab GTPases at a glance" 128 : 3171-3176, 2015
• 105 Ibáñez P, "Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease" 364 : 1169-1171, 2004
• 106 설원기, "Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson’s disease" 생화학분자생물학회 43 (43): 233-244, 2010
• 107 Lu CS, "Analysis of the LRRK2 Gly2385Arg variant in primary dystonia and multiple system atrophy in Taiwan" 14 : 393-396, 2008
• 108 Takagawa T, "An increase in LRRK2suppresses autophagy and enhances Dectin-1-induced immunity in a mouse model of colitis" 10 : eaan8162-, 2018
• 109 Rivero-Ríos P, "Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked Parkinson’s disease" 43 : 390-395, 2015
• 110 Chartier-Harlin MC, "Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease" 364 : 1167-1169, 2004
• 111 Spillantini MG, "Alpha-synuclein in Lewy bodies" 388 : 839-840, 1997
• 112 Cooper AA, "Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models" 313 : 324-328, 2006
• 113 Krüger R, "Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease" 18 : 106-108, 1998
• 114 Porras P, "A visual review of the interactome of LRRK2 : using deep-curated molecular interaction data to represent biology" 15 : 1390-1404, 2015
• 115 Funayama M, "A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1" 51 : 296-301, 2002
• 116 Zimprich A, "A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease" 89 : 168-175, 2011
• 117 Chang D, "A meta-analysis of genomewide association studies identifies 17 new Parkinson’s disease risk loci" 49 : 1511-1516, 2017
• 118 Di Fonzo A, "A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease" 365 : 412-415, 2005
• 119 Di Fonzo A, "A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson’s disease risk in Taiwan" 7 : 133-138, 2006
• 120 Gilks WP, "A common LRRK2 mutation in idiopathic Parkinson’s disease" 365 : 415-416, 2005
• 121 Soukup SF, "A LRRK2-dependent endophilinA phosphoswitch is critical for macroautophagy at presynaptic terminals" 92 : 829-844, 2016