阿爾茲海默症與帕金森氏症是目前兩個最盛行的神經性退化疾病，但由於我們對於疾病認知的限制，仍然未開發出有效的治療方式，目前只有數個已知變異會導致疾病的基因，因此許多研究都聚焦於全基因組關連研究(GWAS)來發現更多的致病基因。在這篇研究中，我們使用了果蠅的複眼系統去測試近期研究中發表與阿爾茲海默症和帕金森氏症相關的基因，在表現人類的tau 蛋白及amyloid-beta 42蛋白的果蠅中提高或降低相關基因的表現量，我們在實驗中證實了果蠅的複眼表現性狀的改變。在研究中我們發現過去被認為與amyloid- beta 42蛋白有關的基因PSEN2、CLU、PICALM、PLD3，可能也與tau蛋白的毒性有關聯，而我們的研究也發現MEF2C可能與amyloid-beta 42的毒性有相關。另外我們在與帕金森氏症相關基因的實驗中，也推論出其病因可能與受損的溶體有關係。

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most prevalent neurodegeneration disorders, but our understanding to these diseases is limited. With only a few pathological-related genes being identified, many studies now focus on finding more genes by genome-wide association study (GWAS). In this study, we used Drosophila eye model to test AD and PD associated genes reported in some recent studies. By up- and down-regulating several genes in fly carrying human tau or amyloid-beta 42 (Aβ42), we verified experimentally the phenotypes of the eyes. Our results reveal that some of the genes reported to interact with Aβ42, including PSEN2, CLU, PICALM and PLD3, also mediate tau toxicity, and MEF2C gene shows modifications in Aβ42. PD associated genes identifying suggests the pathogenesis relating to lysosome dysfunction.

Beach, T. G., Monsell, S. E., Phillips, L. E., & Kukull, W. (2012). Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol, 71(4), 266-273. doi: 10.1097/NEN.0b013e31824b211b
Boyle, M., Nighorn, A., & Thomas, J. B. (2006). Drosophila Eph receptor guides specific axon branches of mushroom body neurons. Development, 133(9), 1845-1854. doi: 10.1242/dev.02353
Cruchaga, C., Karch, C. M., Jin, S. C., Benitez, B. A., Cai, Y., Guerreiro, R., . . . Goate, A. M. (2014). Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature, 505(7484), 550-554. doi: 10.1038/nature12825
Dehay, B., Bove, J., Rodriguez-Muela, N., Perier, C., Recasens, A., Boya, P., & Vila, M. (2010). Pathogenic lysosomal depletion in Parkinson's disease. J Neurosci, 30(37), 12535-12544. doi: 10.1523/jneurosci.1920-10.2010
DeMattos, R. B., Cirrito, J. R., Parsadanian, M., May, P. C., O'Dell, M. A., Taylor, J. W., . . . Holtzman, D. M. (2004). ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron, 41(2), 193-202.
Dietrich, J. B. (2013). The MEF2 family and the brain: from molecules to memory. Cell Tissue Res, 352(2), 179-190. doi: 10.1007/s00441-013-1565-2
Grabowski, G. A. (2008). Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet, 372(9645), 1263-1271. doi: 10.1016/S0140-6736(08)61522-6
Grunewald, A., Arns, B., Seibler, P., Rakovic, A., Munchau, A., Ramirez, A., . . . Klein, C. (2012). ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome. Neurobiol Aging, 33(8), 1843 e1841-1847. doi: 10.1016/j.neurobiolaging.2011.12.035
Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science, 297(5580), 353-356. doi: 10.1126/science.1072994
Hermle, T., Guida, M. C., Beck, S., Helmstadter, S., & Simons, M. (2013). Drosophila ATP6AP2/VhaPRR functions both as a novel planar cell polarity core protein and a regulator of endosomal trafficking. EMBO J, 32(2), 245-259. doi: 10.1038/emboj.2012.323
Holemans, T., Sorensen, D. M., van Veen, S., Martin, S., Hermans, D., Kemmer, G. C., . . . Vangheluwe, P. (2015). A lipid switch unlocks Parkinson's disease-associated ATP13A2. Proc Natl Acad Sci U S A, 112(29), 9040-9045. doi: 10.1073/pnas.1508220112
Karch, C. M., Cruchaga, C., & Goate, A. M. (2014). Alzheimer's disease genetics: from the bench to the clinic. Neuron, 83(1), 11-26. doi: 10.1016/j.neuron.2014.05.041
Kaushik, S., & Cuervo, A. M. (2012). Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol, 22(8), 407-417. doi: 10.1016/j.tcb.2012.05.006
Lahiri, D. K., Ge, Y. W., Rogers, J. T., Sambamurti, K., Greig, N. H., & Maloney, B. (2006). Taking down the unindicted co-conspirators of amyloid beta-peptide-mediated neuronal death: shared gene regulation of BACE1 and APP genes interacting with CREB, Fe65 and YY1 transcription factors. Curr Alzheimer Res, 3(5), 475-483.
Lambert, J. C., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., . . . Amouyel, P. (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet, 45(12), 1452-1458. doi: 10.1038/ng.2802
Larsson, M., Duffy, D. L., Zhu, G., Liu, J. Z., Macgregor, S., McRae, A. F., . . . Medland, S. E. (2011). GWAS findings for human iris patterns: associations with variants in genes that influence normal neuronal pattern development. Am J Hum Genet, 89(2), 334-343. doi: 10.1016/j.ajhg.2011.07.011
Liu, G., Chen, M., Mi, N., Yang, W., Li, X., Wang, P., . . . Yu, S. (2015). Increased oligomerization and phosphorylation of alpha-synuclein are associated with decreased activity of glucocerebrosidase and protein phosphatase 2A in aging monkey brains. Neurobiol Aging, 36(9), 2649-2659. doi: 10.1016/j.neurobiolaging.2015.06.004
Luzio, J. P., Pryor, P. R., & Bright, N. A. (2007). Lysosomes: fusion and function. Nat Rev Mol Cell Biol, 8(8), 622-632. doi: 10.1038/nrm2217
Maxfield, F. R., & Yamashiro, D. J. (1987). Endosome acidification and the pathways of receptor-mediated endocytosis. Adv Exp Med Biol, 225, 189-198.
Nalls, M. A., Pankratz, N., Lill, C. M., Do, C. B., Hernandez, D. G., Saad, M., . . . Singleton, A. B. (2014). Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet, 46(9), 989-993. doi: 10.1038/ng.3043
Shulman, J. M., Imboywa, S., Giagtzoglou, N., Powers, M. P., Hu, Y., Devenport, D., . . . Feany, M. B. (2014). Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms. Hum Mol Genet, 23(4), 870-877. doi: 10.1093/hmg/ddt478
Shulman, L. M., Gruber-Baldini, A. L., Anderson, K. E., Vaughan, C. G., Reich, S. G., Fishman, P. S., & Weiner, W. J. (2008). The evolution of disability in Parkinson disease. Mov Disord, 23(6), 790-796. doi: 10.1002/mds.21879
Sly, L. M., Ho, V., Antignano, F., Ruschmann, J., Hamilton, M., Lam, V., . . . Krystal, G. (2007). The role of SHIP in macrophages. Front Biosci, 12, 2836-2848.
Verstraeten, A., Theuns, J., & Van Broeckhoven, C. (2015). Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet, 31(3), 140-149. doi: 10.1016/j.tig.2015.01.004
Xiao, Q., Gil, S. C., Yan, P., Wang, Y., Han, S., Gonzales, E., . . . Lee, J. M. (2012). Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis. J Biol Chem, 287(25), 21279-21289. doi: 10.1074/jbc.M111.338376