Chemical genetic approach identifies microtubule affinity-regulating kinase 1 as a leucine-rich repeat kinase 2 substrate

FASEB Journal

Volumn 29, Issue 7, 2015, Pages 2980-2992

  Krumova, Petranka ^a   Reyniers, Lauran ^b   Meyer, Marc ^a   Lobbestael, Evy ^b   Stauffer, Daniela ^a   Gerrits, Bertran ^a   Muller, Lionel ^a   Hoving, Sjouke ^a   Kaupmann, Klemens ^a   Voshol, Johannes ^a   Fabbro, Doriano ^a   Bauer, Andreas ^a   Rovelli, Giorgio ^a   Taymans, Jean Marc ^b,c   Bouwmeester, Tewis ^a   Baekelandt, Veerle ^b  

^a NOVARTIS PHARMA AG   (Switzerland)

^b KU LEUVEN UNIVERSITY OF LEUVEN   (Belgium)

^c JEAN PIERRE AUBERT RESEARCH CENTER   (France)

Author keywords

Cellular signaling; Gatekeeper kinase; Neuroscience; Parkinson's disease

Indexed keywords

ADENOSINE TRIPHOSPHATE DERIVATIVE; ALANINE; LEUCINE RICH REPEAT KINASE 2; METHIONINE; MICROTUBULE AFFINITY REGULATING KINASE 1; MICROTUBULE ASSOCIATED PROTEIN 2; MICROTUBULE ASSOCIATED PROTEIN 4; MICROTUBULE PROTEIN; PROTEIN SERINE THREONINE KINASE; REGULATOR PROTEIN; TAU PROTEIN; UNCLASSIFIED DRUG; LRRK2 PROTEIN, HUMAN; LRRK2 PROTEIN, MOUSE; MARK1 PROTEIN, HUMAN; MARK1 PROTEIN, MOUSE; MUTANT PROTEIN; RECOMBINANT PROTEIN;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; AUTORADIOGRAPHY; BINDING SITE; CELL CYCLE REGULATION; CHEMICAL GENETICS; CONTROLLED STUDY; DELETION MUTANT; EMBRYO; ENERGY RESOURCE; ENZYME PHOSPHORYLATION; ENZYME SUBSTRATE; EUKARYOTIC CELL; GENE EXPRESSION; GENETIC IDENTIFICATION; GENETIC SCREENING; HUMAN; HUMAN CELL; IMMUNOPRECIPITATION; IN VITRO STUDY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; WESTERN BLOTTING; AMINO ACID SEQUENCE; ANIMAL; BRAIN; CHEMISTRY; DEFICIENCY; ENZYME SPECIFICITY; GENETICS; HEK293 CELL LINE; KNOCKOUT MOUSE; METABOLISM; MICROTUBULE; MOLECULAR GENETICS; PARKINSON DISEASE;

EUKARYOTA; PYRONIA TITHONUS;

AMINO ACID SEQUENCE; ANIMALS; BRAIN; HEK293 CELLS; HUMANS; MICE; MICE, KNOCKOUT; MICROTUBULES; MOLECULAR SEQUENCE DATA; MUTANT PROTEINS; PARKINSON DISEASE; PROTEIN-SERINE-THREONINE KINASES; RECOMBINANT PROTEINS; SUBSTRATE SPECIFICITY;

EID: 84940421908     PISSN: 08926638     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.14-262329     Document Type: Article

References (68)

1. Lees, A. J., Hardy, J., and Revesz, T. (2009)Parkinson'sdisease.Lancet 373, 2055-2066.
2. Tsuboi, Y. (2012) Environmental-genetic interactions in the pathogenesis of Parkinson's disease. Exp. Neurobiol. 21, 123-128.
3. Schulte, C., and Gasser, T. (2011) Genetic basis of Parkinson's disease: inheritance, penetrance, and expression. Appl. Clin. Genet. 4, 67-80.
4. Pais̈an-Rúiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simon, J., van der Brug, M., Ĺopez de Munain, A., Aparicio, S., Gil, A.M., Khan, N., Johnson, J., Martinez, J. R., Nicholl, D., Carrera, I.M., Pena, A. S., de Silva, R., Lees, A., Marti-Mass̈o, J.-F., Perez-Tur, J., Wood, N. W., and Singleton, A. B. (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600.
5. Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carbajal, I. C., Vieregge, P., Asmus, F., Müller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., and Gasser, T. (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607.
6. Satake, W., Nakabayashi, Y., Mizuta, I., Hirota, Y., Ito, C., Kubo, M., Kawaguchi, T., Tsunoda, T., Watanabe, M., Takeda, A., Tomiyama, H., Nakashima, K., Hasegawa, K., Obata, F., Yoshikawa, T., Kawakami, H., Sakoda, S., Yamamoto, M., Hattori, N., Murata, M., Nakamura, Y., and Toda, T. (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat. Genet. 41, 1303-1307.
7. Simon-͆anchez, J., Schulte, C., Bras, J. M., Sharma, M., Gibbs, J. R., Berg, D., Paisan-Ruiz, C., Lichtner, P., Scholz, S. W., Hernandez, D. G., Krüger, R., Federoff, M., Klein, C., Goate, A., Perlmutter, J., Bonin, M., Nalls, M. A., Illig, T., Gieger, C., Houlden, H., Steffens, M., Okun, M. S., Racette, B. A., Cookson, M.R., Foote, K.D., Fernandez, H.H., Traynor, B. J., Schreiber, S., Arepalli, S., Zonozi, R., Gwinn, K., van der Brug, M., Lopez, G., Chanock, S. J., Schatzkin, A., Park, Y., Hollenbeck, A., Gao, J., Huang, X., Wood, N.W., Lorenz, D., Deuschl, G., Chen, H., Riess, O., Hardy, J. A., Singleton, A. B., and Gasser, T. (2009)Genomewide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308-1312.
8. Rideout, H. J., and Stefanis, L. (2014) The neurobiology of LRRK2 and its role in the pathogenesis of Parkinson's disease. Neurochem. Res. 39, 576-592.
9. Greggio, E., Jain, S., Kingsbury, A., Bandopadhyay, R., Lewis, P., Kaganovich, A., van der Brug, M. P., Beilina, A., Blackinton, J., Thomas, K. J., Ahmad, R., Miller, D.W., Kesavapany, S., Singleton, A., Lees, A., Harvey, R. J., Harvey, K., and Cookson, M.R. (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol. Dis. 23, 329-341.
10. 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.
11. West, A. B., Moore, D. J., Biskup, S., Bugayenko, A., Smith, W. W., Ross, C. A., Dawson, V. L., and Dawson, T. M. (2005) Parkinson's disease-associatedmutations in leucine-rich repeat kinase 2 augment kinase activity. Proc.Natl. Acad. Sci. USA 102, 16842-16847.
12. Danïels, V., Baekelandt, V., and Taymans, J.-M. (2011)Onthe roadto leucine-rich repeat kinase 2 signalling: evidence fromcellular and in vivo studies. Neurosignals 19, 1-15.
13. Greggio, E. (2012) Role of LRRK2 kinase activity in the pathogenesis of Parkinson's disease. Biochem. Soc. Trans. 40, 1058-1062.
14. Jaleel, M., Nichols, R. J., Deak, M., Campbell, D. G., Gillardon, F., Knebel, A., and Alessi, D.R. (2007)LRRK2 phosphorylatesmoesinat threonine-558: characterization of how Parkinson's diseasemutants affect kinase activity. Biochem. J. 405, 307-317.
15. Parisiadou, L., Xie, C., Cho, H. J., Lin, X., Gu, X.-L., Long, C.-X., Lobbestael, E., Baekelandt, V., Taymans, J.-M., Sun, L., and Cai, H. (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J. Neurosci. 29, 13971-13980.
16. Zach, S., Felk, S., and Gillardon, F. (2010) Signal transduction protein array analysis linksLRRK2 to Ste20 kinases and PKCzeta that modulate neuronal plasticity. PLoS One 5, e13191.
17. Martin, I., Kim, J. W., Lee, B. D., Kang, H. C., Xu, J. C., Jia, H., Stankowski, J., Kim, M. S., Zhong, J., Kumar, M., Andrabi, S. A., Xiong, Y., Dickson, D.W., Wszolek, Z. K., Pandey, A., Dawson, T.M., and Dawson, V. L. (2014) Ribosomal protein s15 phosphorylation mediatesLRRK2 neurodegenerationin Parkinson'sdisease. Cell 157, 472-485.
18. Gloeckner, C. J., Schumacher, A., Boldt, K., and Ueffing, M. (2009) The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro. J. Neurochem. 109, 959-968.
19. Hsu, C. H., Chan, D., Greggio, E., Saha, S., Guillily, M. D., Ferree, A., Raghavan, K., Shen, G. C., Segal, L., Ryu, H., Cookson, M. R., and Wolozin, B. (2010) MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2. J. Neurochem. 112, 1593-1604.
20. Ohta, E., Kawakami, F., Kubo, M., and Obata, F. (2011) LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: impairment of the kinase activity by Parkinson's disease-associated mutations. FEBS Lett. 585, 2165-2170.
21. 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.
22. Kumar, A., Greggio, E., Beilina, A., Kaganovich, A., Chan, D., Taymans, J.-M., Wolozin, B., and Cookson, M. R. (2010) The Parkinson's disease associated LRRK2 exhibits weaker in vitro phosphorylation of 4E-BP compared to autophosphorylation. PLoS One 5, e8730.
23. Bailey, R.M., Covy, J. P., Melrose, H. L., Rousseau, L., Watkinson, R., Knight, J., Miles, S., Farrer, M. J., Dickson, D.W., Giasson, B. I., and Lewis, J. (2013) LRRK2 phosphorylates novel tau epitopes and promotes tauopathy. Acta Neuropathol. 126, 809-827.
24. Gillardon, F. (2009) Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability-a point of convergence in parkinsonian neurodegeneration? J. Neurochem. 110, 1514-1522.
25. Kawakami, F., Yabata, T., Ohta, E., Maekawa, T., Shimada, N., Suzuki, M., Maruyama, H., Ichikawa, T., and Obata, F. (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.
26. Law, B. M.H., Spain, V. A., Leinster, V.H. L., Chia, R., Beilina, A., Cho, H. J., Taymans, J. M., Urban, M. K., Sancho, R. M., Blanca Ramírez, M., Biskup, S., Baekelandt, V., Cai, H., Cookson, M. R., Berwick, D. C., and Harvey, K. (2014) A direct interaction between leucine-rich repeat kinase 2 and specific b-tubulin isoforms regulates tubulin acetylation. J. Biol. Chem. 289, 895-908.
27. Allen, J. J., Li, M., Brinkworth, C. S., Paulson, J. L., Wang, D., Hübner, A., Chou, W. H., Davis, R. J., Burlingame, A. L., Messing, R. O., Katayama, C. D., Hedrick, S. M., and Shokat, K. M. (2007) A semisynthetic epitope for kinase substrates. Nat. Methods 4, 511-516.
28. Cravatt, B. F. (2005) Kinase chemical genomics-a new rule for the exceptions. Nat. Methods 2, 411-412.
29. Banko, M.R., Allen, J. J., Schaffer, B.E., Wilker, E.W., Tsou, P., White, J.L., Vilĺen, J., Wang, B., Kim, S.R., Sakamoto, K., Gygi, S. P., Cantley, L. C., Yaffe, M. B., Shokat, K. M., and Brunet, A. (2011) Chemical genetic screen for AMPKa2 substrates uncovers a network of proteins involved in mitosis. Mol. Cell 44, 878-892.
30. Blasius, M., Forment, J. V., Thakkar, N., Wagner, S. A., Choudhary, C., and Jackson, S. P. (2011) A phospho-proteomic screen identifies substrates of the checkpoint kinase Chk1. Genome Biol. 12, R78.
31. Blethrow, J. D., Glavy, J. S., Morgan, D.O., and Shokat, K.M. (2008) Covalent capture of kinase-specific phosphopeptides reveals Cdk1- cyclin B substrates. Proc.Natl. Acad. Sci. USA 105, 1442-1447.
32. Chi, Y., Welcker, M., Hizli, A. A., Posakony, J. J., Aebersold, R., and Clurman, B. E. (2008) Identification of CDK2 substrates in human cell lysates. Genome Biol. 9, R149.
33. Schauble, S., King, C. C., Darshi, M., Koller, A., Shah, K., and Taylor, S. S. (2007) Identification of ChChd3 as a novel substrate of the cAMP-dependent protein kinase (PKA) using an analog-sensitive catalytic subunit. J. Biol. Chem. 282, 14952-14959.
34. Drewes, G., Ebneth, A., Preuss, U., Mandelkow, E. M., and Mandelkow, E. (1997) MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89, 297-308.
35. Ibrahimi, A., Vande Velde, G., Reumers, V., Toelen, J., Thiry, I., Vandeputte, C., Vets, S., Deroose, C., Bormans, G., Baekelandt, V., Debyser, Z., and Gijsbers, R. (2009) Highly efficient multicistronic lentiviral vectors with peptide 2A sequences. Hum. Gene Ther. 20, 845-860.
36. Herzig, M. C., Kolly, C., Persohn, E., Theil, D., Schweizer, T., Hafner, T., Stemmelen, C., Troxler, T. J., Schmid, P., Danner, S., Schnell, C. R., Mueller, M., Kinzel, B., Grevot, A., Bolognani, F., Stirn, M., Kuhn, R. R., Kaupmann, K., van der Putten, P. H., Rovelli, G., and Shimshek, D. R. (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.
37. Sengle, G., Jenne, A., Arora, P. S., Seelig, B., Nowick, J. S., Jaschke, A., and Famulok, M. (2000) Synthesis, incorporation efficiency, and stability ofdisulfide bridged functional groups atRNA5'-ends.Bioorg. Med Chem. 8, 1317 -1329.
38. Geraerts, M., Michiels, M., Baekelandt, V., Debyser, Z., Gijsbers, R. (2005) Upscaling of lentiviral vector production by tangential flow filtration. J. Gene Med. 7, 1299-1310.
39. Taymans, J. M., Gao, F., and Baekelandt, V. (2013) Metabolic labeling of leucine rich repeat kinases 1 and 2 with radioactive phosphate. J. Vis. Exp. 79, e50523.
40. Chen, H., Chan, B. K., Drummond, J., Estrada, A. A., Gunzner-Toste, J., Liu, X., Liu, Y., Moffat, J., Shore, D., Sweeney, Z.K., Tran, T., Wang, S., Zhao, G., Zhu, H., and Burdick, D. J. (2012)Discovery of selective LRRK2 inhibitors guided by computational analysis and molecular modeling. J. Med. Chem. 55, 5536-5545.
41. Vancraenenbroeck, R., Lobbestael, E., Maeyer, M. D., Baekelandt, V., and Taymans, J.-M. (2011) Kinases as targets for Parkinson's disease: fromgenetics to therapy. CNS Neurol. Disord. Drug Targets 10, 724-740.
42. Hiriyanna, K. T., Baedke, D., Baek, K.H., Forney, B. A., Kordiyak, G., and Ingebritsen, T. S. (1994) Thiophosphorylated substrate analogs are potent active site-directed inhibitors of protein-tyrosine phosphatases. Anal. Biochem. 223, 51-58.
43. Lobbestael, E., Baekelandt, V., and Taymans, J.-M. (2012) Phosphorylation of LRRK2: from kinase to substrate. Biochem. Soc. Trans. 40, 1102-1110.
44. Lizcano, J. M., Göransson, O., Toth, R., Deak, M., Morrice, N. A., Boudeau, J., Hawley, S. A., Udd, L., Mäkelä, T. P., Hardie, D. G., and Alessi, D.R. (2004)LKB1 is amaster kinase that activates 13 kinases of the AMPK subfamily, includingMARK/PAR-1. EMBO J. 23, 833-843.
45. Matenia, D., and Mandelkow, E. M. (2009) The tau of MARK: A polarized view of the cytoskeleton. Trends Biochem. Sci. 34, 332-342.
46. Timm, T., Balusamy, K., Li, X., Biernat, J., Mandelkow, E., and Mandelkow, E.-M. (2008) Glycogen synthase kinase (GSK) 3beta directly phosphorylates Serine 212 in the regulatory loop and inhibits microtubule affinity-regulating kinase (MARK) 2. J. Biol. Chem. 283, 18873-18882.
47. Timm, T., Li, X.-Y., Biernat, J., Jiao, J., Mandelkow, E., Vandekerckhove, J., and Mandelkow, E.-M. (2003) MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1. EMBO J. 22, 5090-5101.
48. Timm, T., Marx, A., Panneerselvam, S., Mandelkow, E., and Mandelkow, E. M. (2008) Structure and regulation of MARK, a kinase involved in abnormal phosphorylation of Tau protein. BMC Neurosci. 9(Suppl 2), S9.
49. Sun, T. Q., Lu, B., Feng, J. J., Reinhard, C., Jan, Y.N., Fantl, W. J., and Williams, L. T. (2001) PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling. Nat. Cell Biol. 3, 628-636.
50. Ossipova, O., Dhawan, S., Sokol, S., and Green, J. B. (2005) Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate development. Dev. Cell 8, 829-841.
51. Plowey, E.D., Cherra III, S. J., 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.
52. 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.
53. Sheng, Z., Zhang, S., Bustos, D., Kleinheinz, T., Le Pichon, C. E., Dominguez, S. L., Solanoy, H. O., Drummond, J., Zhang, X., Ding, X., Cai, F., Song, Q., Li, X., Yue, Z., vanderBrug, M.P., Burdick, D. J., Gunzner-Toste, J., Chen, H., Liu, X., Estrada, A. A., Sweeney, Z. K., Scearce-Levie, K., Moffat, J.G., Kirkpatrick, D. S., and Zhu, H. (2012) Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci. Transl. Med. 4, 164ra161.
54. Dächsel, J. C., Behrouz, B., Yue, M., Beevers, J.E., Melrose, H. L., and Farrer, M. J. (2010)AcomparativestudyofLrrk2functioninprimary neuronal cultures. Parkinsonism Relat. Disord. 16, 650-655.
55. Sepulveda, B., Mesias, R., Li, X., Yue, Z., and Benson, D. L. (2013) Short- And long-term effects of LRRK2 on axonand dendrite growth. PLoS One 8, e61986.
56. Wang, L., Xie, C., Greggio, E., Parisiadou, L., Shim, H., Sun, L., Chandran, J., Lin, X., Lai, C., Yang, W. J., Moore, D. J., Dawson, T.M., Dawson, V. L., Chiosis, G., Cookson, M. R., and Cai, H. (2008) The chaperone activity of heat shock protein 90 is critical formaintaining the stability of leucine-rich repeat kinase 2. J. Neurosci. 28, 3384-3391.
57. Gandhi, P. N., Wang, X., Zhu, X., Chen, S. G., and Wilson-Delfosse, A. L. (2008) The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules. J. Neurosci. Res. 86, 1711-1720.
58. Taymans, J.M., and Cookson, M.R. (2010)Mechanisms indominant parkinsonism:The toxic triangleofLRRK2, alpha-synuclein, andtau. BioEssays 32, 227-235.
59. Gan-Or, Z., Bar-Shira, A., Mirelman, A., Gurevich, T., Giladi, N., and Orr-Urtreger, A. (2012)The age atmotor symptoms onset inLRRK2- Associated Parkinson's disease is affected by a variation in theMAPT locus: A possible interaction. J. Mol. Neurosci. 46, 541-544.
60. Biernacka, J. M., Armasu, S. M., Cunningham, J. M., Ahlskog, J. E., Chung, S. J., and Maraganore, D.M. (2011)Do interactions between SNCA, MAPT, and LRRK2 genes contribute to Parkinson's disease susceptibility? Parkinsonism Relat. Disord. 17, 730-736.
61. Giordana, M. T., D'Agostino, C., Albani, G., Mauro, A., Di Fonzo, A., Antonini, A., and Bonifati, V. (2007)Neuropathology of Parkinson's disease associated with the LRRK2 Ile1371Valmutation.Mov. Disord. 22, 275-278.
62. Puschmann, A., Englund, E., Ross, O. A., Vilariño-Güell, C., Lincoln, S. J., Kachergus, J. M., Cobb, S. A., Törnqvist, A. L., Rehncrona, S., Widner, H., Wszolek, Z. K., Farrer, M. J., and Nilsson, C. (2012) First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation. Parkinsonism Relat. Disord. 18, 332-338.
63. Khan, N. L., Jain, S., Lynch, J. M., Pavese, N., Abou-Sleiman, P., Holton, J. L., Healy, D. G., Gilks, W. P., Sweeney, M. G., Ganguly, M., Gibbons, V., Gandhi, S., Vaughan, J., Eunson, L.H., Katzenschlager, R., Gayton, J., Lennox, G., Revesz, T., Nicholl, D., Bhatia, K. P., Quinn, N., Brooks, D., Lees, A. J., Davis, M. B., Piccini, P., Singleton, A. B., and Wood, N. W. (2005) Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 128, 2786-2796.
64. Rajput, A., Dickson, D.W., Robinson, C.A., Ross, O.A., Dächsel, J. C., Lincoln, S. J., Cobb, S. A., Rajput, M. L., and Farrer, M. J. (2006) Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 67, 1506-1508.
65. Ujiie, S., Hatano, T., Kubo, S., Imai, S., Sato, S., Uchihara, T., Yagishita, S., Hasegawa, K., Kowa, H., Sakai, F., and Hattori, N. (2012) LRRK2 I2020T mutation is associated with tau pathology. Parkinsonism Relat. Disord. 18, 819-823.
66. Melrose, H. L., Dächsel, J. C., Behrouz, B., Lincoln, S. J., Yue, M., Hinkle, K. M., Kent, C. B., Korvatska, E., Taylor, J. P., Witten, L., Liang, Y. Q., Beevers, J. E., Boules, M., Dugger, B. N., Serna, V. A., Gaukhman, A., Yu, X., Castanedes-Casey, M., Braithwaite, A. T., Ogholikhan, S., Yu, N., Bass, D., Tyndall, G., Schellenberg, G. D., Dickson, D. W., Janus, C., and Farrer, M. J. (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol. Dis. 40, 503-517.
67. Herzig, M. C., Bidinosti, M., Schweizer, T., Hafner, T., Stemmelen, C., Weiss, A., Danner, S., Vidotto, N., Stauffer, D., Barske, C., Mayer, F., Schmid, P., Rovelli, G., van der Putten, P. H., and Shimshek, D. R. (2012) High LRRK2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain. PLoS One 7, e36581.
68. Lin, C. H., Tsai, P. I., Wu, R. M., and Chien, C. T. (2010) LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3ß. J. Neurosci. 30, 13138-13149.