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 APD  Vol.5 No.1 , February 2016
Inhibition of foxo and minibrain in Dopaminergic Neurons Can Model Aspects of Parkinson Disease in Drosophila melanogaster
Abstract: Symptoms of Parkinson Disease (PD), the second most common neurodegenerative disease, emerge due to degeneration of dopaminergic neurons. Recently, a genome wide study revealed a role for a foxo transcription factor in PD. In the model organism Drosophila melanogaster, we have attempted 1) to inhibit the sole Drosophila homologue of foxo through the directed expression of a stable inducible RNAi transgene and 2) to indirectly increase foxo transcription activity through the inhibition of the kinase minibrain (mnb), a foxo transcriptional inhibitor. To evaluate the lifetime consequences upon the flies, longevity assays and locomotion over time assays were conducted. The inhibition of foxo by foxo-RNAi decreases life span significantly when expressed under the control of Tyrosine Hydroxylase-Gal4 (TH-Gal4). The targeted expression of mnb-RNAi, in the dopaminergic neurons, with an expected loss of suppression of foxo transcriptional activity, results in a significant loss of climbing ability. Thus alteration of foxo activity, both by RNA-inhibition and by down-regulation of an inhibitor of foxo, minibrain, produces novel Drosophila models of Parkinson Disease.
Cite this paper: Chavoshi, M.S. and Staveley, B.E. (2016) Inhibition of foxo and minibrain in Dopaminergic Neurons Can Model Aspects of Parkinson Disease in Drosophila melanogaster. Advances in Parkinson's Disease, 5, 1-6. doi: 10.4236/apd.2016.51001.
References

[1]   Schiesling, C., Kieper, N., Seidel, K. and Krüger R. (2008) Familial Parkinson’s Disease Genetics, Clinical Phenotype and Neuropathology in Relation to the Common Sporadic Form of the Disease. Neuropathology and Applied Neurobiology, 34, 255-271.
http://dx.doi.org/10.1111/j.1365-2990.2008.00952.x

[2]   Dumitriu, A., Latourelle, J.C., Hadzi, T.C., Pankratz, N., Garza, D., Miller, J.P., et al. (2012) Gene Expression Profiles in Parkinson Disease Prefrontal Cortex Implicate FOXO1 and Genes under Its Transcriptional Regulation. PLoS Genetics, 8, Article ID: 1002794.
http://dx.doi.org/10.1371/journal.pgen.1002794

[3]   Eijkelenboom, A. and Burgering, B.M.T. (2013) FOXOs: Signalling Integrators for Homeostasis Maintenance. Nature Reviews in Molecular Cell Biology, 14, 83-97. http://dx.doi.org/10.1038/nrm3507

[4]   Calnan, D.R. and Brunet, A. (2008) The FoxO Code. Oncogene, 27, 2276-2288.
http://dx.doi.org/10.1038/onc.2008.21

[5]   Perens, E.A. and Shaham, S. (2005) C. elegans daf-6 Encodes a Patched-Related Protein Required for Lumen Formation. Developmental Cell, 8, 893-906. http://dx.doi.org/10.1016/j.devcel.2005.03.009

[6]   Kramer, J.M., Davidge, J.T., Lockyer, J.M. and Staveley, B.E. (2003) Expression of Drosophila FOXO Regulates Growth and Can Phenocopy Starvation. BioMed Central Developmental Biology, 3, 5.
http://dx.doi.org/10.1186/1471-213X-3-5

[7]   Brunet, A., Bonni, A., Zigmond, M.J., Lin, M.Z., Juo, P., Hu, L.S., et al. (1999) Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor. Cell, 96, 857-868.
http://dx.doi.org/10.1016/S0092-8674(00)80595-4

[8]   Woods, Y.L., Rena, G., Morrice, N., Barthel, A., Becker, W., Guo, S., et al. (2001) The Kinase DYRK1A Phosphorylates the Transcription Factor FKHR at Ser329 in Vitro, a Novel in Vivo Phosphorylation Site. Biochemical Journal, 355, 597-607. http://dx.doi.org/10.1042/bj3550597

[9]   Tejedor, F., Zhu, X.R., Kaltenbach, E., Ackermann, A., Baumann, A., Canal, I., et al. (1995) Minibrain: A New Protein Kinase Family Involved in Postembryonic Neurogenesis in Drosophila. Neuron, 14, 287-301. http://dx.doi.org/10.1016/0896-6273(95)90286-4

[10]   Hong, S.H., Lee, K.S., Kwak, S.J., Kim, A.K., Bai, H., Jung, M.S., et al. (2012) Minibrain/Dyrk1a Regulates Food Intake Through the Sir2-FOXO-sNPF/NPY Pathway in Drosophila and Mammals. PLoS Genetics, 8, Article ID: 1002857. http://dx.doi.org/10.1371/journal.pgen.1002857

[11]   Staveley, B.E. (2014) Drosophila Models of Parkinson Disease. In: LeDoux, M.S., Ed., Movement Disorders: Genetics and Models, 2nd Edition, Elsevier Inc., Amsterdam, The Netherlands, 345-354.

[12]   Staveley, B.E. (2012) Successes of Modelling Parkinson Disease in Drosophila. In: Dushanova, J., Ed., Mechanisms in Parkinson’s Disease—Models and Treatments, InTech Inc., Rijeka, Croatia, 233-250.

[13]   Feany, M.B. and Bender, W.W. (2000) A Drosophila Model of Parkinson’s Disease. Nature, 404, 394-398. http://dx.doi.org/10.1038/35006074

[14]   Greene, J.C., Whitworth, A.J., Kuo, I., Andrews, L.A., Feany, M.J. and Pallanck, L.J. (2003) Mitochondrial Pathology and Apoptotic Muscle Degeneration in Drosophila Parkin Mutants. Proceeding of the National Academy Sciences USA, 100, 4078-4083. http://dx.doi.org/10.1073/pnas.0737556100

[15]   Haywood, A.F.M. and Staveley, B.E. (2004) Parkin Counteracts Symptoms in a Drosophila Model of Parkinson’s Disease. BioMed Central Neuroscience, 5, 14. http://dx.doi.org/10.1186/1471-2202-5-14

[16]   Clark, I.E., Dodson, M.W., Jiang, C., Cao, J.H., Huh, J.R., Seol, J.H., et al. (2006) Drosophila Pink1 Is Required for Mitochondrial Function and Interacts Genetically with Parkin. Nature, 441, 1162-1166.

[17]   Park, J., Lee, S.B., Lee, S., Kim, Y., Song, S., Kim, S., et al., (2006) Mitochondrial Dysfunction in Drosophila PINK1 Mutants Is Complemented by Parkin. Nature, 441, 1157-1161.
http://dx.doi.org/10.1038/nature04788

[18]   Todd, A.M. and Staveley, B.E. (2008) Pink1 Suppresses Alpha-Synuclein-Induced Phenotypes in a Drosophila Model of Parkinson’s Disease. Genome, 51, 1040-1046. http://dx.doi.org/10.1139/G08-085

[19]   Staveley, B.E., Phillips, J.P. and Hilliker, A.J. (1990) Phenotypic Consequences of Copper-Zinc Superoxide-Dismutase Overexpression in Drosophila melanogaster. Genome, 33, 867-872.
http://dx.doi.org/10.1139/g90-130

[20]   Todd, A.M. and Staveley, B.E. (2004) Novel Assay and Analysis for Measuring Climbing Ability in Drosophila. Drosophila Information Service, 87, 101-108.

[21]   Li, H., Chaneya, S., Forteb, M. and Hirsh, J. (2000) Ectopic G-Protein Expression in Dopamine and Serotonin Neurons Blocks Cocaine Sensitization in Drosophila melanogaster. Current Biology, 10, 211-214. http://dx.doi.org/10.1016/S0960-9822(00)00340-7

[22]   Alic, N., Hoddinott, M.P., Foley, A., Slack, C., Piper, M. and Partridge, L. (2012) Detrimental Effects of RNAi: A Cautionary Note on Its Use in Drosophila Ageing Studies. PLoS ONE, 7, Article ID: 45367.
http://dx.doi.org/10.1371/journal.pone.0045367

 
 
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