[Frontiers in Bioscience, Landmark, 25, 159-167, Jan 1, 2020]

Targeting UCH in Drosophila melanogaster as a model for Parkinson’s disease

Dang Thi Phuong Thao1

1Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu St, Dist 5, Ho Chi Minh City, Vietnam

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Drosophila model of PD targeting to UCH-L1
    3.1. Molecular competence of Drosophila model of PD with a focus on UCH-L1
    3.2. Parkinson’s disease symptoms and PD–like phenotypes in knockdown dUCH fly model
      3.2.1. The dUCH knockdown fly model exhibited the PD-like phenotype of movement
      3.2.2. dUCH knockdown fly model displayed the PD-like phenotype of DA neuron degeneration
      3.2.3. The PD-like phenotype of aging-dependent progression in the dUCH knockdown fly model
      3.2.4. The PD-like phenotype of a dopamine shortage in the dUCH knockdown fly model
4. Conclusion and perspective
5. Acknowledgment
6. References

1. ABSTRACT

Parkinson’s disease (PD) is a neurodegenerative disease caused by genetic or environmental factors. Among several animal models, the Drosophila melanogaster is one of the valuable models widely used in studying genes and proteins implicated in PD. UCH-L1 (Ubiquitin carboxyl-terminal hydrolase L1) which is involved in formation of Lewy bodies, shows loss of function mutations in PD causing degeneration of dopaminergic neurons in mice. Here, we summarize the results from studying the UCH-L1 and its knockdown in Drosophila model of PD with respect to movement, degeneration of dopamine producing neurons, dopamine deficiency and age dependent dependency of progression of the disease. The knockdown of the UCH-L1 in Drosophila can be used in studying the epidemiology of the disease as well as in drug screening for finding therapeutic targets for PD.

6. REFERENCES

1. Ross, C. A. & Smith, W. W. Gene-environment interactions in Parkinson's disease. Parkinsonism & related disorders 13 Suppl 3, S309-315, (2007)
DOI: 10.1016/S1353-8020(08)70022-1

2. Goldwurm, S., M. Zini, L. Mariani, S. Tesei, R. Miceli, F. Sironi, M. Clementi, V. Bonifati, and G. Pezzoli. Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease. Neurology 68, 1141-1143, (2007)
DOI: 10.1212/01.wnl.0000254483.19-854.ef
PMid:17215492

3. Lim, K.-L. and C.-H. Ng, Genetic models of Parkinson disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1792(7): p. 604-615 (2009)
DOI: 10.1016/j.bbadis.2008.10.005
PMid:19000757

4. Dawson, T.M., H.S. Ko, and V.L. Dawson, Genetic animal models of Parkinson's disease. Neuron, 66(5): p. 646-61 (2010)
DOI: 10.1016/j.neuron.2010.04.034
PMid:20547124 PMCid:PMC2917798

5. Jagmag, S. A., Tripathi, N., Shukla, S. D., Maiti, S., & Khurana, S., Evaluation of Models of Parkinson's Disease. Front Neurosci 9(503) (2016)
DOI: 10.3389/fnins.2015.00503
PMid:26834536 PMCid:PMC4718050

6. Whitworth, A.J., Drosophila models of Parkinson's disease. Adv Genet, 73, 1-50. (2011)
DOI: 10.1016/B978-0-12-380860-8.00001-X
PMid:21310293

7. Blanco, J., Pandey, R., Wasser, M. & Udolph, G. Orthodenticle is necessary for survival of a cluster of clonally related dopaminergic neurons in the Drosophila larval and adult brain. Neural Dev 6, 34, (2011)
DOI: 10.1186/1749-8104-6-34
PMid:21999236 PMCid:PMC3206411

8. White, K. E., Humphrey, D. M. & Hirth, F. The dopaminergic system in the aging brain of Drosophila. Front Neurosci 4, 205, (2010)
DOI: 10.3389/fnins.2010.00205
PMid:21165178 PMCid:PMC3002484

9. Lowe, J., McDermott, H., Landon, M., Mayer, R. J. & Wilkinson, K. D. Ubiquitin carboxyl-terminal hydrolase (PGP 9.5) is selectively present in ubiquitinated inclusion bodies characteristic of human neurodegenerative diseases. J Pathol, 161, 153-160, (1990)
DOI: 10.1002/path.1711610210
PMid:2166150

10. Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein, M.J., Jonnalagada, S., Chernova, T. and Dehejia, A. The ubiquitin pathway in Parkinson's disease. Nature 395, 451-452, (1998)
DOI: 10.1038/26652
PMid:9774100

11. Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z. & Lansbury, P. T., Jr. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 111, 209-218 (2002)
DOI: 10.1016/S0092-8674(02)01012-7

12. Maraganore, D.M., Lesnick, T.G., Elbaz, A., Chartier-Harlin, M.C., Gasser, T., Krüger, R., Hattori, N., Mellick, G.D., Quattrone, A., Satoh, J.I. and Toda, T. UCHL1 is a Parkinson's disease susceptibility gene. Annals Neurol 55, 512-521, (2004)
DOI: 10.1002/ana.20017
PMid:15048890

13. Belin, A.C., Westerlund, M., Bergman, O., Nissbrandt, H., Lind, C., Sydow, O. and Galter, D., S18Y in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) associated with decreased risk of Parkinson's disease in Sweden. Parkinsonism & related disorders 13, 295-298, (2007)
DOI: 10.1016/j.parkreldis.2006.12.002
PMid:17287139

14. Larsen, C. N., Price, J. S. & Wilkinson, K. D. Substrate binding and catalysis by ubiquitin C-terminal hydrolases: identification of two active site residues. Biochemistry 35, 6735-6744, (1996)
DOI: 10.1021/bi960099f
PMid:8639624

15. Case, A. & Stein, R. L. Mechanistic studies of ubiquitin C-terminal hydrolase L1. Biochemistry 45, 2443-2452, (2006)
DOI: 10.1021/bi052135t
PMid:16475834

16. Boudreaux, D. A., Maiti, T. K., Davies, C. W. & Das, C. Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation. Proc Natl Acad Sci 107, 9117-9122, (2010)
DOI: 10.1073/pnas.0910870107
PMid:20439756 PMCid:PMC2889082

17. Bilguvar, K., Tyagi, N.K., Ozkara, C., Tuysuz, B., Bakircioglu, M., Choi, M., Delil, S., Caglayan, A.O., Baranoski, J.F., Erturk, O. and Yalcinkaya, C. Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. Proc Natl Acad Sci 110, 3489-3494, (2013)
DOI: 10.1073/pnas.1222732110
PMid:23359680 PMCid:PMC3587195

18. Misaghi, S., Galardy, P.J., Meester, W.J., Ovaa, H., Ploegh, H.L. and Gaudet, R. Structure of the ubiquitin hydrolase UCH-L3 complexed with a suicide substrate. J Biol Chem 280, 1512-1520, (2005)
DOI: 10.1074/jbc.M410770200
PMid:15531586

19. Forno, L.S., Neuropathology of Parkinson's disease. J Neuropathol & Exp Neurology, 55(3): 259-272 (1996)
DOI: 10.1097/00005072-199603000-00001
PMid:8786384

20. Feany, M.B. and W.W. Bender, A Drosophila model of Parkinson's disease. Nature, 404(6776): 394-8. (2000)
DOI: 10.1038/35006074
PMid:10746727

21. Liu, Z., Wang, X., Yu, Y.I., Li, X., Wang, T., Jiang, H., Ren, Q., Jiao, Y., Sawa, A., Moran, T. and Ross, C.A, A Drosophila model for LRRK2-linked parkinsonism. Proc Natl Acad Sci, 105(7) 2693-8 (2008)
DOI: 10.1073/pnas.0708452105
PMid:18258746 PMCid:PMC2268198

22. Imai, Y., Gehrke, S., Wang, H.Q., Takahashi, R., Hasegawa, K., Oota, E. and Lu, B. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. The EMBO J, 2008. 27(18): p. 2432-2443 (2008)
DOI: 10.1038/emboj.2008.163
PMid:18701920 PMCid:PMC2543051

23. Nassel, D.R. and K. Elekes, Aminergic neurons in the brain of blowflies and Drosophila: dopamine- and tyrosine hydroxylase-immunoreactive neurons and their relationship with putative histaminergic neurons. Cell Tissue Res, 267(1): 147-67 (1992)
DOI: 10.1007/BF00318701
PMid:1346506

24. Mao, Z. and R.L. Davis, Eight Different Types of Dopaminergic Neurons Innervate the Drosophila Mushroom Body Neuropil: Anatomical and Physiological Heterogeneity. Frontiers in Neural Circuits, 3, 5, (2009)
DOI: 10.3389/neuro.04.005.2009
PMid:19597562 PMCid:PMC2708966

25. Budnik, V. and K. White, Catecholamine-containing neurons in Drosophila melanogaster: distribution and development. J Comp Neurol, 268(3): p. 400-13 (1998)
DOI: 10.1002/cne.902680309
PMid:3129458

26. Jankovic, J., Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry, 79(4), 368-76 (1998)
DOI: 10.1136/jnnp.2007.131045
PMid:18344392

27. Budnik, V. & White, K. Catecholamine-containing neurons in Drosophila melanogaster: distribution and development. The . J Comp Neurol 268, 400-413, (1988)
DOI: 10.1002/cne.902680309
PMid:3129458

Key Words: Fly PD model, Parkinson disease, PD-like symptoms, Drug screening, Review

Send correspondence: Dang Thi Phuong Thao, Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu St, Dist 5, Ho Chi Minh City, Vietnam, Tel: 084 28 8307079, E-mail: dtpthao@hcmus.edu.vn