Insights into LRRK2 function and dysfunction from transgenic and knockout rodent models

Biochemical Society Transactions

Volumn 40, Issue 5, 2012, Pages 1080-1085

  Sloan, Maximilian ^a   Alegre Abarrategui, Javier ^a   Wade Martins, Richard ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Autophagy; Cytoskeleton; Dopamine; Leucine rich repeat kinase 2 (LRRK2); Parkinson's disease; Tau

Indexed keywords

ALPHA SYNUCLEIN; BETA TUBULIN; LEUCINE RICH REPEAT KINASE 2; TAU PROTEIN; TUMOR NECROSIS FACTOR;

ACTIN FILAMENT; AUTOPHAGY; CELL MIGRATION; CELL STRUCTURE; CELL VACUOLE; DOPAMINERGIC NERVE CELL; ENZYME ACTIVITY; GENE MUTATION; GENE SILENCING; GOLGI COMPLEX; HOMEOSTASIS; HUMAN; NERVE FIBER GROWTH; NEURITE; NONHUMAN; PARKINSON DISEASE; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REVIEW;

ANIMALS; DISEASE MODELS, ANIMAL; GENE DELETION; MICE; MICE, KNOCKOUT; MICE, TRANSGENIC; PARKINSON DISEASE; PROTEIN-SERINE-THREONINE KINASES;

RODENTIA;

EID: 84866694018     PISSN: 03005127     EISSN: 14708752     Source Type: Journal    
DOI: 10.1042/BST20120151     Document Type: Review

References (50)

1. Berg, D., Schweitzer, K.J., Leitner, P., Zimprich, A., Lichtner, P., Belcredi, P., Brussel, T., Schulte, C., Maass, S., Nagele, T. et al. (2005) Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease. Brain 128, 3000-3011
2. Mata, I.F., Wedemeyer, W.J., Farrer, M.J., Taylor, J.P. and Gallo, K.A. (2006) LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci, 29, 286-293
3. Greggio, E., Zambrano, I., Kaganovich, A., Beilina, A., Taymans, J.-M., Daniels, V., Lewis, P., Jain, S., Ding, J., Syed, 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
4. Lin, X., Parisiadou, L., Gu, X.L., Wang, L.Z., Shim, H., Sun, L.X., Xie, C.S., Long, C.X., Yang, W.J., Ding, J.H. et al. (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant α-synuclein. Neuron 64, 807-827
5. Gillardon, F. (2009) Leucine-rich repeat kinase 2 phosphorylates brain tubulin-β isoforms and modulates microtubule stability: a point of convergence in Parkinsonian neurodegeneration? J. Neurochem. 110, 1514-1522
6. Kett, L.R., Boassa, D., Ho, C.C.Y., Rideout, H.J., Hu, J.R., Terada, M., Ellisman, M. and Dauer, W.T. (2012) LRRK2 Parkinson disease mutations enhance its microtubule association. Hum. Mol. Genet. 21, 890-899
7. Parisiadou, L., Xie, C.S., Cho, H.J., Lin, X., Gu, X.L., Long, C.X., Lobbestael, E., Baekelandt, V., Taymans, J.-M., Sun, L.X. and Cai, H.B. (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J. Neurosci. 29, 13971-13980
8. Piccoli, G., Condliffe, S.B., Bauer, M., Giesert, F., Boldt, K., De Astis, S., Meixner, A., Sarioglu, H., Vogt-Weisenhorn, D.M., Wurst, W. et al. (2011) LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool. J. Neurosci. 31, 2225-2237
9. Shin, N., Jeong, H., Kwon, J., Heo, H.Y., Kwon, J.J., Yun, H.J., Kim, C.H., Han, B.S., Tong, Y., Shen, J. et al. (2008) LRRK2 regulates synaptic vesicle endocytosis. Exp. Cell Res. 314, 2055-2065
10. Tong, Y.R., Giaime, E., Yamaguchi, H., Ichimura, T., Liu, Y.M., Si, H.Q., Cai, H.B., 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, 1-16
11. Herzig, M.C., Kolly, C., Persohn, E., Theil, D., Schweizer, T., Hafner, T., Stemmelen, C., Troxler, T.J., Schmid, P., Danner, S. 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
12. Tong, Y., Yamaguchi, H., Giaime, E., Boyle, S., Kopan, R., Kelleher, 3rd, R.J. 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. U.S.A. 107, 9879-9884
13. 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
14. Harvey, B.K., Wang, Y. and Hoffer, B.J. (2008) Transgenic rodent models of Parkinson's disease. Acta Neurochir. Suppl. 101, 89-92
15. Winner, B., Melrose, H.L., Zhao, C., Hinkle, K.M., Yue, M., Kent, C., Braithwaite, A.T., Ogholikhan, S., Aigner, R., Winkler, J. et al. (2011) Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol. Dis. 41, 706-716
16. 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
17. Dachsel, J.C., Behrouz, B., Yue, M., Beevers, J.E., Melrose, H.L. and Farrer, M.J. (2010) A comparative study of Lrrk2 function in primary neuronal cultures. Parkinsonism Relat. Disord. 16, 650-655
18. Ramonet, D., Daher, J.P., Lin, B.M., Stafa, K., Kim, J., Banerjee, R., Westerlund, M., Pletnikova, O., Glauser, L., Yang, L. et al. (2011) Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS ONE 6, e18568
19. 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
20. Wang, L.Z., Xie, C.S., Greggio, E., Parisiadou, L., Shim, H., Sun, L.X., Chandran, J., Lin, X., Lai, C., Yang, W.J. et al. (2008) The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2. J. Neurosci. 28, 3384-3391
21. Meixner, A., Boldt, K., Van Troys, M., Askenazi, M., Gloeckner, C.J., Bauer, M., Marto, J.A., Ampe, C., Kinkl, N. and Ueffing, M. (2011) A QUICK screen for Lrrk2 interaction partners: leucine-rich repeat kinase 2 is involved in actin cytoskeleton dynamics. Mol. Cell. Proteomics 10, 1-17
22. Lee, B.D., Shin, J.H., VanKampen, J., Petrucelli, L., West, A.B., Ko, H.S., Lee, Y.I., Maguire-Zeiss, K.A., Bowers, W.J., Federoff, H.J. et al. (2010) Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nat. Med. 16, 998-1000
23. Kim, B., Yang, M.S., Choi, D., Kim, J.H., Kim, H.S., Seol, W., Jou, I., Kim, E.Y. and Joe, E. (2011) Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia. Glia 59, S141-S142
24. Neumann, H., Schweigreiter, R.D., Yamashita, T., Rosenkranz, K., Wekerle, H. and Barde, Y.A. (2002) Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a Rho-dependent mechanism. J. Neurosci. 22, 854-862
25. Vora, P. and McGovern, D.P.B. (2012) LRRK2 as a negative regulator of NFAT: implications for the pathogenesis of inflammatory bowel disease. Expert Rev. Clin. Immunol. 8, 227-229
26. Parisiadou, L. and Cai, H. (2010) LRRK2 function on actin and microtubule dynamics in Parkinson disease. Commun. Integr. Biol. 3, 396-400
27. Gard, D.L. and Kirschner, M.W. (1985) A polymer-dependent increase in phosphorylation of β-tubulin accompanies differentiation of a mouse neuroblastoma cell line. J. Cell Biol. 100, 764-774
28. Ren, Y., Liu, W.H., Jiang, H.B., Jiang, Q. and Feng, J. (2005) Selective vulnerability of dopaminergic neurons to microtubule depolymerization. J. Biol. Chem. 280, 34105-34112
29. Santpere, G. and Ferrer, I. (2009) LRRK2 and neurodegeneration. Acta Neuropathol. 117, 227-246
30. Edwards, T.L., Scott, W.K., Almonte, C., Burt, A., Powell, E.H., Beecham, G.W., Wang, L.Y., Zuchner, S., Konidari, I., Wang, G.F. et al. (2010) Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann. Hum. Genet. 74, 97-109
31. Brandt, R., Leger, J. and Lee, G. (1995) Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain. J. Cell Biol. 131, 1327-1340
32. Dusonchet, J., Kochubey, O., Stafa, K., Young, S.M., 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
33. Li, Y.P., Liu, W.C., Oo, T.F., Wang, L., Tang, Y., Jackson-Lewis, V., Zhou, C., Geghman, K., Bogdanov, M., Przedborski, S. et al. (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat. Neurosci. 12, 826-828
34. Melrose, H.L., Dachsel, J.C., Behrouz, B., Lincoln, S.J., Yue, M., Hinkle, K.M., Kent, C.B., Korvatska, E., Taylor, J.P., Witten, L. et al. (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol. Dis. 40, 503-517
35. 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
36. Jameson, L., Frey, T., Zeeberg, B., Dalldorf, F. and Caplow, M. (1980) Inhibition of microtubule assembly by phosphorylation of microtubule-associated proteins. Biochemistry 19, 2472-2479
37. Mutez, E., Larvor, L., Lepretre, F., Mouroux, V., Hamalek, D., Kerckaert, J.P., Perez-Tur, J., Waucquier, N., Vanbesien-Mailliot, C., Duflot, A. et al. (2011) Transcriptional profile of Parkinson blood mononuclear cells with LRRK2 mutation. Neurobiol. Aging 32, 1839-1848
38. Dent, E.W. and Kalil, K. (2001) Axon branching requires interactions between dynamic microtubules and actin filaments. J. Neurosci. 21, 9757-9769
39. Chen, C.Y., Weng, Y.H., Chien, K.Y., Lin, K.J., Yeh, T.H., Cheng, Y.P., Lu, C.S. and Wang, H.L. (2012) (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell Death Differ. doi:10.1038/cdd.2012.42
40. Zhou, H., Huang, C., Tong, J., Hong, W.C., Liu, Y.J. and Xia, X.G. (2011) Temporal expression of mutant LRRK2 in adult rats impairs dopamine reuptake. Int. J. Biol. Sci. 7, 753-761
41. Li, X.T., Patel, J.C., Wang, J., Avshalumov, M.V., Nicholson, C., Buxbaum, J.D., Elder, G.A., Rice, M.E. and Yue, Z.Y. (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
42. Tong, Y.R., 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. U.S.A. 106, 14622-14627
43. Biskup, S., Moore, D.J., Celsi, F., Higashi, S., West, A.B., Andrabi, S.A., Kurkinen, K., Yu, S.W., Savitt, J.M., Waldvogel, H.J. et al. (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann. Neurol. 60, 557-569
44. 11C-raclopride and positron emission tomography. Ann. Neurol. 31, 184-192
45. 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
46. Gómez-Suaga, P. and Hilfiker, S. (2012) LRRK2 as a modulator of lysosomal calcium homeostasis with downstream effects on autophagy. Autophagy 8, 692-693
47. Hamano, T., Gendron, T.F., Causevic, E., Yen, S.H., Lin, W.L., Isidoro, C., DeTure, M. and Ko, L.W. (2008) Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur. J. Neurosci. 27, 1119-1130
48. Daher, J.P., Pletnikova, O., Biskup, S., Musso, A., Gellhaar, S., Galter, D., Troncoso, J.C., Lee, M.K., Dawson, T.M., Dawson, V.L. and Moore, D.J. (2012) Neurodegenerative phenotypes in an A53T α-synuclein transgenic mouse model are independent of LRRK2. Hum. Mol. Genet. 21, 2420-2431
49. Webb, J.L., Ravikumar, B., Atkins, J., Skepper, J.N. and Rubinsztein, D.C. (2003) α-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009-25013
50. Esteves, A.R., Arduino, D.M., Swerdlow, R.H., Oliveira, C.R. and Cardoso, S.M. (2010) Microtubule depolymerization potentiates α-synuclein oligomerization. Front. Aging Neurosci. 1, 5