APD  Vol.4 No.3 , August 2015
LDN-73794 Attenuated LRRK2-Induced Degeneration in a Drosophila Parkinson’s Disease Model
ABSTRACT
Parkinson’s disease (PD) is a common neurodegenerative disease with unclear pathogenesis. Currently, there are no disease-modifying neuron-protecting drugs to slow down the neuronal degeneration. Mutations in the leucine-rich repeat kinase 2 (LRRK2) cause genetic forms of PD and contribute to sporadic PD as well. Disruption of LRRK2 kinase functions has become one of the potential mechanisms underlying disease-linked mutation-induced neuronal degeneration. To further characterize the pharmacological effects of a reported LRRK2 kinase inhibitor, LDN-73794, in vitro cell models and a LRRK2 Drosophila PD model were used. LDN-73794 reduced LRRK2 kinase activity in vitro and in vivo. Moreover, LDN-73794 increased survival, improved locomotor activity, and suppressed DA neuron loss in LRRK2 transgenic flies. These results suggest that inhibition of LRRK2 kinase activity can be a potential therapeutic strategy for PD intervention and LDN-73794 could be a potential lead compound for developing neuroprotective therapeutics.

Cite this paper
Yang, D. , Das, S. , Song, L. , Li, T. , Yan, J. and Smith, W. (2015) LDN-73794 Attenuated LRRK2-Induced Degeneration in a Drosophila Parkinson’s Disease Model. Advances in Parkinson's Disease, 4, 49-58. doi: 10.4236/apd.2015.43007.
References
[1]   Paisan-Ruiz, C., Jain, S., Evans, E.W., Gilks, W.P., Simon, J., van der, B.M., Lopez, D.M., 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-Masso, 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. http://dx.doi.org/10.1016/j.neuron.2004.10.023

[2]   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., Muller-Myhsok, B., Dickson, D.W., Meitinger, T., Strom, T.M., Wszolek, Z.K. and Gasser, T. (2004) Mutations in LRRK2 Cause Autosomal-Domi- nant Parkinsonism with Pleomorphic Pathology. Neuron, 44, 601-607.
http://dx.doi.org/10.1016/j.neuron.2004.11.005

[3]   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 Neuroscience, 8, 102. http://dx.doi.org/10.1186/1471-2202-8-102

[4]   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. Proceedings of the National Academy of Sciences of the USA, 102, 18676-18681. http://dx.doi.org/10.1073/pnas.0508052102

[5]   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., Faull, R.L., Emson, P.C., Torp, R., Ottersen, O.P., Dawson, T.M. and Dawson, V.L. (2006) Localization of LRRK2 to Membranous and Vesicular Structures in Mammalian Brain. Annals of Neurology, 60, 557-569.
http://dx.doi.org/10.1002/ana.21019

[6]   Moehle, M.S., Webber, P.J., Tse, T., Sukar, N., Standaert, D.G., De Silva, T.M., Cowell, R.M. and West, A.B. (2012) LRRK2 Inhibition Attenuates Microglial Inflammatory Responses. Journal of Neuroscience, 32, 1602-1611.
http://dx.doi.org/10.1523/JNEUROSCI.5601-11.2012

[7]   Zhu, X., Siedlak, S.L., Smith, M.A., Perry, G. and Chen, S.G. (2006) LRRK2 Protein Is a Component of Lewy Bodies. Annals of Neurology, 60, 617-618.
http://dx.doi.org/10.1002/ana.20928

[8]   Mac Leod, 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. http://dx.doi.org/10.1016/j.neuron.2006.10.008

[9]   Sakaguchi-Nakashima, A., Meir, J.Y., Jin, Y., Matsumoto, K. and Hisamoto, N. (2007) LRK-1, a C. elegans PARK8- Related Kinase, Regulates Axonal-Dendritic Polarity of SV Proteins. Current Biology, 17, 592-598. http://dx.doi.org/10.1016/j.cub.2007.01.074

[10]   Sheng, D., Qu, D., Kwok, K.H., Ng, S.S., Lim, A.Y., Aw, S.S., Lee, C.W., Sung, W.K., Tan, E.K., Lufkin, T., Jesuthasan, S., Sinnakaruppan, M. and Liu, J. (2010) Deletion of the WD40 Domain of LRRK2 in Zebrafish Causes Parkinsonism-Like Loss of Neurons and Locomotive Defect. PLOS Genetics, 6, e1000914. http://dx.doi.org/10.1371/journal.pgen.1000914

[11]   Lee, S.B., Kim, W., Lee, S. and Chung, J. (2007) Loss of LRRK2/PARK8 Induces Degeneration of Dopaminergic Neurons in Drosophila. Biochemical and Biophysical Research Communications, 358, 534-539. http://dx.doi.org/10.1016/j.bbrc.2007.04.156

[12]   Cookson, M.R. (2010) The Role of Leucine-Rich Repeat Kinase 2 (LRRK2) in Parkinson’s Disease. Nature Reviews Neuroscience, 11, 791-797. http://dx.doi.org/10.1038/nrn2935

[13]   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 Mediates LRRK2 Neurodegeneration in Parkinson’s Disease. Cell, 157, 472-485.
http://dx.doi.org/10.1016/j.cell.2014.01.064

[14]   Cookson, M.R., Dauer, W., Dawson, T., Fon, E.A., Guo, M. and Shen, J. (2007) The Roles of Kinases in Familial Parkinson’s Disease. The Journal of Neuroscience, 27, 11865-11868.
http://dx.doi.org/10.1523/JNEUROSCI.3695-07.2007

[15]   Moore, D.J. (2008) The Biology and Pathobiology of LRRK2: Implications for Parkinson’s Disease. Parkinsonism & Related Disorders, 14, S92-S98.
http://dx.doi.org/10.1016/j.parkreldis.2008.04.010

[16]   Gandhi, P.N., Chen, S.G. and Wilson-Delfosse, A.L. (2009) Leucine-Rich Repeat Kinase 2 (LRRK2): A Key Player in the Pathogenesis of Parkinson’s Disease. Journal of Neuroscience Research, 87, 1283-1295. http://dx.doi.org/10.1002/jnr.21949

[17]   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-Associated Mutations in Leucine-Rich Repeat Kinase 2 Augment Kinase Activity. Proceedings of the National Academy of Sciences of the United States of America, 102, 16842-16847. http://dx.doi.org/10.1073/pnas.0507360102

[18]   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. Nature Neuroscience, 9, 1231-1233.
http://dx.doi.org/10.1038/nn1776

[19]   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. Biochemical Journal, 405, 307-317.
http://dx.doi.org/10.1042/BJ20070209

[20]   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. The EMBO Journal, 27, 2432-2443. http://dx.doi.org/10.1038/emboj.2008.163

[21]   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. Journal of Neurochemistry, 109, 959-968.
http://dx.doi.org/10.1111/j.1471-4159.2009.06024.x

[22]   Tan, E.K. and Schapira, A.H. (2010) LRRK2 as a Therapeutic Target in Parkinson’s Disease. European Journal of Neurology, 18, 545-546.

[23]   Lee, B.D., Shin, J.H., Van Kampen, J., Petrucelli, L., West, A.B., Ko, H.S., Lee, Y.I., Maguire-Zeiss, K.A., Bowers, W.J., Federoff, H.J., Dawson, V.L. and Dawson, T.M. (2010) Inhibitors of Leucine-Rich Repeat Kinase-2 Protect against Models of Parkinson’s Disease. Nature Medicine, 16, 998-1000. http://dx.doi.org/10.1038/nm.2199

[24]   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 Genetics, 6, e1000902. http://dx.doi.org/10.1371/journal.pgen.1000902

[25]   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. Neurobiology of Disease, 23, 329-341. http://dx.doi.org/10.1016/j.nbd.2006.04.001

[26]   Luzon-Toro, B., de la Torre, E.R., Delgado, A., Perez-Tur, J. and Hilfiker, S. (2007) Mechanistic Insight into the Dominant Mode of the Parkinson’s Disease-Associated G2019S LRRK2 Mutation. Human Molecular Genetics, 16, 2031-2039.
http://dx.doi.org/10.1093/hmg/ddm151

[27]   Liu, Z., Hamamichi, S., Dae, L.B., Yang, D., Ray, A., Caldwell, G.A., Caldwell, K.A., Dawson, T.M., Smith, W.W. and Dawson, V.L. (2011) Inhibitors of LRRK2 Kinase Attenuate Neurodegeneration and Parkinson-Like Phenotypes in Caenorhabditis elegans and Drosophila Parkinson’s Disease Models. Human Molecular Genetics, 20, 3933-3942.
http://dx.doi.org/10.1093/hmg/ddr312

[28]   Yang, D., Li, T., Liu, Z., Arbez, N., Yan, J., Moran, T.H., Ross, C.A. and Smith, W.W. (2012) LRRK2 Kinase Activity Mediates Toxic Interactions between Genetic Mutation and Oxidative Stress in a Drosophila Model: Suppression by Curcumin. Neurobiology of Disease, 47, 385-392. http://dx.doi.org/10.1016/j.nbd.2012.05.020

[29]   Deng, X., Dzamko, N., Prescott, A., Davies, P., Liu, Q., Yang, Q., Lee, J.D., Patricelli, M.P., Nomanbhoy, T.K., Alessi, D.R. and Gray, N.S. (2011) Characterization of a Selective Inhibitor of the Parkinson’s Disease Kinase LRRK2. Nature Chemical Biology, 7, 203-205.
http://dx.doi.org/10.1038/nchembio.538

[30]   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. http://dx.doi.org/10.1021/bi901851y

[31]   Liu, M., Poulose, S., Schuman, E., Zaitsev, A.D., Dobson, B., Auerbach, K., Seyb, K., Cuny, G.D., Glicksman, M.A., Stein, R.L. and Yue, Z. (2010) Development of a Mechanism-Based High-Throughput Screen Assay for Leucine-Rich Repeat Kinase 2—Discovery of LRRK2 Inhibitors. Analytical Biochemistry, 404, 186-192.
http://dx.doi.org/10.1016/j.ab.2010.05.033

[32]   Deng, X., Choi, H.G., Buhrlage, S.J. and Gray, N.S. (2012) Leucine-Rich Repeat Kinase 2 Inhibitors: A Patent Review. Expert Opinion on Therapeutic Patents, 22, 1415-1426.
http://dx.doi.org/10.1517/13543776.2012.729041

[33]   Li, T., Yang, D., Zhong, S., Thomas, J.M., Xue, F., Liu, J., Kong, L., Voulalas, P., Hassan, H.E., Park, J.S., MacKerell Jr., A.D. and Smith, W.W. (2014) Novel LRRK2 GTP-Binding Inhibitors Reduced Degeneration in Parkinson’s Disease Cell and Mouse Models. Human Molecular Genetics, 23, 6212-6222.

[34]   Liu, Z., Wang, X., Yu, Y., Li, X., Wang, T., Jiang, H., Ren, Q., Jiao, Y., Sawa, A., Moran, T., Ross, C.A., Montell, C. and Smith, W.W. (2008) A Drosophila Model for LRRK2-Linked Parkinsonism. Proceedings of the National Academy of Sciences of the United States of America, 105, 2693-2698. http://dx.doi.org/10.1073/pnas.0708452105

[35]   Li, X., Moore, D.J., Xiong, Y., Dawson, T.M. and Dawson, V.L. (2010) Reevaluation of Phosphorylation Sites in the Parkinson Disease-Associated Leucine-Rich Repeat Kinase 2. The Journal of Biological Chemistry, 285, 29569-29576.
http://dx.doi.org/10.1074/jbc.M110.127639

[36]   Li, T., Yang, D., Sushchky, S., Liu, Z. and Smith, W.W. (2011) Models for LRRK2-Linked Parkinsonism. Parkinson’s Disease, 2011, Article ID: 942412.
http://dx.doi.org/10.4061/2011/942412

[37]   Kumari, U. and Tan, E.K. (2009) LRRK2 in Parkinson’s Disease: Genetic and Clinical Studies from Patients. FEBS Journal, 276, 6455-6463.
http://dx.doi.org/10.1111/j.1742-4658.2009.07344.x

[38]   Iaccarino, C., Crosio, C., Vitale, C., Sanna, G., Carri, M.T. and Barone, P. (2007) Apoptotic Mechanisms in Mutant LRRK2-Mediated Cell Death. Human Molecular Genetics, 16, 1319-1326. http://dx.doi.org/10.1093/hmg/ddm080

 
 
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