LRRK2 pathobiology in Parkinson's disease

Journal of Neurochemistry

Volumn 131, Issue 5, 2014, Pages 554-565

  Martin, Ian ^a   Kim, Jungwoo Wren ^a   Dawson, Valina L ^a,b   Dawson, Ted M ^a,b,c  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b ADRIENNE HELIS MALVIN MEDICAL RESEARCH FOUNDATION   (United States)

^c Diana Helis Henry Medical Research Foundation   (United States)

Author keywords

Alpha synuclein; GTPase; Kinase; Neurodegeneration; Protein translation; Rps15

Indexed keywords

ALPHA SYNUCLEIN; ENZYME INHIBITOR; GUANOSINE TRIPHOSPHATASE; LEUCINE RICH REPEAT KINASE 2; LEUCINE RICH REPEAT KINASE 2 INHIBITOR; MESSENGER RNA; RAF PROTEIN; RAS PROTEIN; SERINE; THREONINE; TRANSCRIPTION ELONGATION FACTOR; TRANSCRIPTION ELONGATION FACTOR EF1A; UNCLASSIFIED DRUG; LRRK2 PROTEIN, HUMAN; PROTEIN SERINE THREONINE KINASE; SYNUCLEIN;

AUTOPHAGY; AUTOPHOSPHORYLATION; BINDING AFFINITY; CELL DEATH; CYTOSKELETON; DIMERIZATION; DOPAMINERGIC NERVE CELL; DRUG ACTIVITY; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; HETEROZYGOSITY; HOMOZYGOSITY; LEWY BODY; MUTATIONAL ANALYSIS; NEUROTOXICITY; NONHUMAN; PARKINSON DISEASE; PATHOGENESIS; PROTEIN DOMAIN; PROTEIN SYNTHESIS; PROTEIN TRANSPORT; REVIEW; VESICULAR TRAFFICKING; GENETICS; HUMAN; METABOLISM; MUTATION; PATHOLOGY;

GTP PHOSPHOHYDROLASES; HUMANS; MUTATION; PARKINSON DISEASE; PROTEIN TRANSPORT; PROTEIN-SERINE-THREONINE KINASES; SYNUCLEINS;

EID: 84915823222     PISSN: 00223042     EISSN: 14714159     Source Type: Journal    
DOI: 10.1111/jnc.12949     Document Type: Review

References (102)

1. Ahmed I., Liang Y., Schools S., Dawson V. L., Dawson T. M. and Savitt J. M. (2012) Development and characterization of a new Parkinson's disease model resulting from impaired autophagy. J. Neurosci. 32, 16503-16509.
2. Alegre-Abarrategui J., Christian H., Lufino M. M., Mutihac R., Venda L. L., Ansorge O. and Wade-Martins R. (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.
3. Beilina A., Rudenko I. N., Kaganovich A. et al. (2014) Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc. Natl Acad. Sci. USA 111, 2626-2631.
4. Berger Z., Smith K. A. and Lavoie M. J. (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.
5. Bhakar A. L., Dolen G. and Bear M. F. (2012) The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35, 417-443.
6. Biosa A., Trancikova A., Civiero L., Glauser L., Bubacco L., Greggio E. and Moore D. J. (2013) GTPase activity regulates kinase activity and cellular phenotypes of Parkinson's disease-associated LRRK2. Hum. Mol. Genet. 22, 1140-1156.
7. Biskup S., Moore D. J., Rea A., Lorenz-Deperieux B., Coombes C. E., Dawson V. L., Dawson T. M. and West A. B. (2007) Dynamic and redundant regulation of LRRK2 and LRRK1 expression. BMC Neurosci. 8, 102.
8. Chartier-Harlin M. C., Dachsel J. C., Vilarino-Guell C. et al. (2011) Translation initiator EIF4G1 mutations in familial Parkinson disease. Am. J. Hum. Genet. 89, 398-406.
9. Choi H. G., Zhang J., Deng X., Hatcher J. M., Patricelli M. P., Zhao Z., Alessi D. R. and Gray N. S. (2012) Brain penetrant LRRK2 inhibitor. ACS Med. Chem. Lett. 3, 658-662.
10. Civiero L., Vancraenenbroeck R., Belluzzi E. et al. (2012) Biochemical characterization of highly purified leucine-rich repeat kinases 1 and 2 demonstrates formation of homodimers. PLoS ONE 7, e43472.
11. Dachsel J. C., Nishioka K., Vilarino-Guell C. et al. (2010) Heterodimerization of Lrrk1-Lrrk 2: implications for LRRK2-associated Parkinson disease. Mech. Ageing Dev. 131, 210-214.
12. Daher J. P., Pletnikova O., Biskup S. et al. (2012) Neurodegenerative phenotypes in an A53T alpha-synuclein transgenic mouse model are independent of LRRK2. Hum. Mol. Genet. 21, 2420-2431.
13. Daher J. P., Volpicelli-Daley L. A., Blackburn J. P., Moehle M. S. and West A. B. (2014) Abrogation of alpha-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc. Natl Acad. Sci. USA 111, 9289-9294.
14. Dodson M. W., 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.
15. Dusonchet J., Kochubey O., Stafa K., Young S. M., Jr, Zufferey R., Moore D. J., Schneider B. L. and Aebischer P. (2011) A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2. J. Neurosci. 31, 907-912.
16. Friedman L. G., Lachenmayer M. L., Wang J., He L., Poulose S. M., Komatsu M., Holstein G. R. and Yue Z. (2012) Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J. Neurosci. 32, 7585-7593.
17. Funayama M., Li Y., Tomiyama H., Yoshino H., Imamichi Y., Yamamoto M., Murata M., Toda T., Mizuno Y. and Hattori N. (2007) Leucinerich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population. Neuro Report 18, 273-275.
18. Fung H. C., Chen C. M., Hardy J., Singleton A. B. and Wu Y. R. (2006) A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan. BMC Neurol. 6, 47.
19. Gehrke S., Imai Y., Sokol N. and Lu B. (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466, 637-641.
20. Giasson B. I., Covy J. P., Bonini N. M., Hurtig H. I., Farrer M. J., Trojanowski J. Q. and Van Deerlin V. M. (2006) Biochemical and pathological characterization of Lrrk2. Ann. Neurol. 59, 315-322.
21. Gillardon F. (2009) Interaction of elongation factor 1-alpha with leucinerich repeat kinase 2 impairs kinase activity and microtubule bundling in vitro. Neuroscience 163, 533-539.
22. Gkogkas C. G., Khoutorsky A., Ran I. et al. (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493, 371-377.
23. Gotthardt K., Weyand M., Kortholt A., Van Haastert P. J. and Wittinghofer A. (2008) Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase. EMBO J. 27, 2239-2249.
24. Greggio E., Zambrano I., Kaganovich A. et al. (2008) The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J. Biol. Chem. 283, 16906-16914.
25. Greggio E., Taymans J. M., Zhen E. Y. et al. (2009) The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites. Biochem. Biophys. Res. Commun. 389, 449-454.
26. Haebig K., Gloeckner C. J., Miralles M. G., Gillardon F., Schulte C., Riess O., Ueffing M., Biskup S. and Bonin M. (2010) ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucinerich repeat kinase 2. PLoS ONE 5, e13762.
27. Hanafusa H., Ishikawa K., Kedashiro S., Saigo T., Iemura S., Natsume T., Komada M., Shibuya H., Nara A. and Matsumoto K. (2011) Leucine-rich repeat kinase LRRK1 regulates endosomal trafficking of the EGF receptor. Nat. Commun. 2, 158.
28. Hatano T., Kubo S., Imai S., Maeda M., Ishikawa K., Mizuno Y. and Hattori N. (2007) Leucine-rich repeat kinase 2 associates with lipid rafts. Hum. Mol. Genet. 16, 678-690.
29. Haugarvoll K., Toft M., Ross O. A., White L. R., Aasly J. O. and Farrer M. J. (2007) Variants in the LRRK1 gene and susceptibility to Parkinson's disease in Norway. Neurosci. Lett. 416, 299-301.
30. Healy D. G., Falchi M., O'Sullivan S. S. et al. (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 7, 583-590.
31. Hershey J. W., Sonenberg N. and Mathews M. B. (2012) Principles of translational control: an overview. Cold Spring Harb. Perspect. Biol. 4:a011528.
32. Herzig M. C., 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.
33. Imai Y., Gehrke S., Wang H. Q., Takahashi R., Hasegawa K., Oota E. and Lu B. (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J. 27, 2432-2443.
34. Ito G., Okai T., Fujino G., Takeda K., Ichijo H., Katada T. and Iwatsubo T. (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.
35. Jaleel M., Nichols R. J., Deak M., Campbell D. G., Gillardon F., Knebel A. and Alessi D. R. (2007) LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem. J. 405, 307-317.
36. Jorgensen N. D., Peng Y., Ho C. C., Rideout H. J., Petrey D., Liu P. and Dauer W. T. (2009) The WD40 domain is required for LRRK2 neurotoxicity. PLoS ONE 4, e8463.
37. Kett L. R. and Dauer W. T. (2012) Leucine-rich repeat kinase 2 for beginners: six key questions. Cold Spring Harb. Perspect. Med. 2, a009407.
38. Klein C. L., Rovelli G., Springer W., Schall C., Gasser T. and Kahle P. J. (2009) Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment. J. Neurochem. 111, 703-715.
39. Korolchuk V. I. and Rubinsztein D. C. (2011) Regulation of autophagy by lysosomal positioning. Autophagy 7, 927-928.
40. Korolchuk V. I., Saiki S., Lichtenberg M. et al. (2011) Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13, 453-460.
41. Lagier-Tourenne C., Polymenidou M., Hutt K. R. et al. (2012) Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat. Neurosci. 15, 1488-1497.
42. Lee B. D., Shin J. H., VanKampen J. et al. (2010) Inhibitors of leucinerich repeat kinase-2 protect against models of Parkinson's disease. Nat. Med. 16, 998-1000.
43. Li Y., Liu W., Oo T. F. et al. (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat. Neurosci. 12, 826-828.
44. Li X., Patel J. C., Wang J., Avshalumov M. V., Nicholson C., Buxbaum J. D., Elder G. A., Rice M. E. and Yue Z. (2010) Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson's disease mutation G2019S. J. Neurosci. 30, 1788-1797.
45. Liao J., Wu C. X., Burlak C. et al. (2014) Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain. Proc. Natl Acad. Sci. USA 111, 4055-4060.
46. Lin X., Parisiadou L., Gu X. L. 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.
47. Liu Z., Wang X., Yu Y. et al. (2008) A Drosophila model for LRRK2-linked parkinsonism. Proc. Natl Acad. Sci. USA 105, 2693-2698.
48. Liu M., Dobson B., Glicksman M. A., Yue Z. and Stein R. L. (2010) Kinetic mechanistic studies of wild-type leucine-rich repeat kinase 2: characterization of the kinase and GTPase activities. Biochemistry 49, 2008-2017.
49. Liu M., Kang S., Ray S., Jackson J., Zaitsev A. D., Gerber S. A., Cuny G. D. and Glicksman M.A. (2011a) Kinetic, mechanistic, and structural modeling studies of truncated wild-type leucine-rich repeat kinase 2 and the G2019S mutant. Biochemistry 50, 9399-9408.
50. Liu Z., Hamamichi S., Lee B. D., Yang D., Ray A., Caldwell G. A., Caldwell K. A., Dawson T. M., Smith W. W. and Dawson V. L. (2011b) Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models. Hum. Mol. Genet. 20, 3933-3942.
51. Liu Z., Lee J., Krummey S., Lu W., Cai H. and Lenardo M. J. (2011c) The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat. Immunol. 12, 1063-1070.
52. Looyenga B. D., Furge K. A., Dykema K. J., Koeman J., Swiatek P. J., Giordano T. J., West A. B., Resau J. H., Teh B. T. and MacKeigan J. P. (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. USA 108, 1439-1444.
53. 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.
54. MacLeod D. A., Rhinn H., Kuwahara T. et al. (2013) RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 77, 425-439.
55. Maekawa T., Mori S., Sasaki Y., Miyajima T., Azuma S., Ohta E. and Obata F. (2012) The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities. Mol. Neurodegener. 7, 15.
56. Martin I., Kim J. W., Lee B. D. et al. (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157, 472-485.
57. Matta S., Van Kolen K., da Cunha R. et al. (2012) LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 75, 1008-1021.
58. Melrose H. L., Dachsel J. C., Behrouz B. et al. (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol. Dis. 40, 503-517.
59. Mills R. D., Mulhern T. D., Liu F., Culvenor J. G. and Cheng H. C. (2014) Prediction of the repeat domain structures and impact of parkinsonism-associated variations on structure and function of all functional domains of leucine-rich repeat kinase 2 (LRRK2). Hum. Mutat. 35, 395-412.
60. Nguyen H. N., Byers B., Cord B. et al. (2011) LRRK2 mutant iPSCderived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267-280.
61. Nikonova E. V., Xiong Y., Tanis K. Q., Dawson V. L., Vogel R. L., Finney E. M., Stone D. J., Reynolds I. J., Kern J. T. and Dawson T. M. (2012) Transcriptional responses to loss or gain of function of the leucine-rich repeat kinase 2 (LRRK2) gene uncover biological processes modulated by LRRK2 activity. Hum. Mol. Genet. 21, 163-174.
62. Niu J., Yu M., Wang C. and Xu Z. (2012) Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via Dynamin-like protein. J. Neurochem. 122, 650-658.
63. Nuytemans K., Bademci G., Inchausti V. et al. (2013) Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease. Neurology 80, 982-989.
64. Orenstein S. J., Kuo S. H., Tasset I. et al. (2013) Interplay of LRRK2 with chaperone-mediated autophagy. Nat. Neurosci. 16, 394-406.
65. Parisiadou L., Xie C., Cho H. J. et al. (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J. Neurosci. 29, 13971-13980.
66. 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.
67. Plowey E. D., Cherra S. J., 3rd, Liu Y. J. and Chu C. T. (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J. Neurochem. 105, 1048-1056.
68. Polymenidou M., Lagier-Tourenne C., Hutt K. R. et al. (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat. Neurosci. 14, 459-468.
69. Rajput A., Dickson D. W., Robinson C. A., Ross O. A., Dächsel J. C., Lincoln S. J., Cobb S. A., Rajput M. L. and Farrerm M. J. (2006) Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 67, 1506-1518.
70. Ray S., Bender S., Kang S., Lin R., Glicksman M. A. and Liu M. (2014) The Parkinson Disease-linked LRRK2 Protein Mutation I2020T Stabilizes an Active State Conformation Leading to Increased Kinase Activity. J. Biol. Chem. 289, 13042-13053.
71. Reinhardt P., Schmid B., Burbulla L. F. et al. (2013) Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12, 354-367.
72. Ross O. A., Toft M., Whittle A. J. et al. (2006) Lrrk2 and lewy body disease. Ann. Neurol. 59, 388-393.
73. Rudenko I. N., Kaganovich A., Hauser D. N., Beylina A., Chia R., Ding J., Maric D., Jaffe H. and Cookson M. R. (2012) The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation. Biochem. J. 446, 99-111.
74. Saha S., Guillily M. D., Ferree A. et al. (2009) LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J. Neurosci. 29, 9210-9218.
75. Satake W., Nakabayashi Y., Mizuta I. et al. (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat. Genet. 41, 1303-1307.
76. Saunders-Pullman R., Barrett M. J., Stanley K. M., Luciano M. S., Shanker V., Severt L., Hunt A., Raymond D., Ozelius L. J. and Bressman S. B. (2010) LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease. Mov. Disord. 25, 2536-2541.
77. Schulte E. C., Ellwanger D. C., Dihanich S. et al. (2014) Rare variants in LRRK1 and Parkinson's disease. Neurogenetics 15, 49-57.
78. Sen S., Webber P. J. and West A. B. (2009) Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. J. Biol. Chem. 284, 36346-36356.
79. Simon-Sanchez J., Schulte C., Bras J. M. et al. (2009) Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308-1312.
80. Skibinski G., Nakamura K., Cookson M. R. and Finkbeiner S. (2014) Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. J. Neurosci. 34, 418-433.
81. Smith W. W., Pei Z., Jiang H., Moore D. J., Liang Y., West A. B., Dawson V. L., Dawson T. M. and Ross C. A. (2005) Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl Acad. Sci. USA 102, 18676-18681.
82. Smith W. W., Pei Z., Jiang H., Dawson V. L., Dawson T. M. and Ross C. A. (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat. Neurosci. 9, 1231-1233.
83. Stafa K., Trancikova A., Webber P. J., Glauser L., West A. B. and Moore D. J. (2012) GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet. 8, e1002526.
84. Stafa K., Tsika E., Moser R. et al. (2014) Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin GTPase superfamily. Hum. Mol. Genet. 23, 2055-2077.
85. Su Y. C. and Qi X. (2013) Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum. Mol. Genet. 22, 4545-4561.
86. Tain L. S., Mortiboys H., Tao R. N., Ziviani E., Bandmann O. and Whitworth A. J. (2009) Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat. Neurosci. 12, 1129-1135.
87. Taylor J. P., Mata I. F. and Farrer M. J. (2006) LRRK2: a common pathway for parkinsonism, pathogenesis and prevention? Trends Mol. Med. 12, 76-82.
88. Taylor J. P., Hulihan M. M., Kachergus J. M. et al. (2007) Leucine-rich repeat kinase 1: a paralog of LRRK2 and a candidate gene for Parkinson's disease. Neurogenetics 8, 95-102.
89. Taymans J. M., Vancraenenbroeck R., Ollikainen P., Beilina A., Lobbestael E., De Maeyer M., Baekelandt V. and Cookson M. R. (2011) LRRK2 kinase activity is dependent on LRRK2 GTP binding capacity but independent of LRRK2 GTP binding. PLoS ONE 6, e23207.
90. Thoreen C. C., Chantranupong L., Keys H. R., Wang T., Gray N. S. and Sabatini D. M. (2012) A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109-113.
91. Tollervey J. R., Curk T., Rogelj B. et al. (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14, 452-458.
92. Tong Y., Pisani A., Martella G., Karouani M., Yamaguchi H., Pothos E. N. and Shen J. (2009) R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proc. Natl Acad. Sci. USA 106, 14622-14627.
93. Tong Y., Yamaguchi H., Giaime E., Boyle S., Kopan R., Kelleher R. J., 3rd and Shen J. (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. USA 107, 9879-9884.
94. Tong Y., Giaime E., Yamaguchi H., Ichimura T., Liu Y., Si H., Cai H., Bonventre J. V. and Shen J. (2012) Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol. Neurodegener. 7, 2.
95. Trancikova A., Mamais A., Webber P. J., Stafa K., Tsika E., Glauser L., West A. B., Bandopadhyay R. and Moore D. J. (2012) Phosphorylation of 4E-BP1 in the mammalian brain is not altered by LRRK2 expression or pathogenic mutations. PLoS ONE 7, e47784.
96. Wang X., Yan M. H., Fujioka H., Liu J., Wilson-Delfosse A., Chen S. G., Perry G., Casadesus G. and Zhu X. (2012) LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum. Mol. Genet. 21, 1931-1944.
97. Webber P. J., Smith A. D., Sen S., Renfrow M. B., Mobley J. A. and West A. B. (2011) Autophosphorylation in the leucine-rich repeat kinase 2 (LRRK2) GTPase domain modifies kinase and GTPbinding activities. J. Mol. Biol. 412, 94-110.
98. West A. B., Moore D. J., Choi C. et al. (2007) Parkinson's diseaseassociated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet. 16, 223-232.
99. Westerlund M., Belin A. C., Anvret A., Bickford P., Olson L. and Galter D. (2008) Developmental regulation of leucine-rich repeat kinase 1 and 2 expression in the brain and other rodent and human organs: implications for Parkinson's disease. Neuroscience 152, 429-436.
100. Xiong Y., Coombes C. E., Kilaru A., Li X., Gitler A. D., Bowers W. J., Dawson V. L., Dawson T. M. and Moore D. J. (2010) GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genet. 6, e1000902.
101. Xiong Y., Yuan C., Chen R., Dawson T. M. and Dawson V. L. (2012) ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2. J. Neurosci. 32, 3877-3886.
102. Zimprich A., Biskup S., Leitner P. et al. (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607.