The mechanism study of the knockdown of ribose-5-phosphate isomerase on polyglutamine toxicity attenuation in Drosophila melanogaster

果蠅核醣-5-磷酸異構酶降低表現量對多麩醯胺酸蛋白毒性減緩作用機轉之研究

黃銘豪(Ming-Hao Huang)

指導教授 ： 汪宏達

國立清華大學/生命科學院/生物科技研究所/碩士(2010年)

摘要

Neurodegenerative diseases are progressive loss of structure and function of neurons leading to neuronal cell death. Polyglutamine (polyQ) tract results from a repeat of CAG trinucleotide and causes irregular protein folding and degradation pathways and altered subcellular localization. The mutant polyQ can cause neurodegenerative diseases, including Huntington’s disease (HD). According to the previous studies, we found that the knockdown of ribose-5-phosphate isomerase (rpi) can rescue the defect fly eye from polyQ toxicity. However, the mechanism behind the effect is still unclear. In this thesis, I used Drosophila as a genetic model to approach this question and test some related possible factors involved in pentose phosphate pathway. In contrast with rpi act as convert ribulose-5-phosphate to ribose-5-phosphate, Ribose-5-phosphate epimerase (rpe) act as convert ribulose-5-phosphate to xylulose-5-phosphate. And protein phosphatase 2 A (PP2A) could be activated by xylulose-5-phosphate which is a intermediate product. I found that rpe and PP2A do not involve in rpi-knockdown mediated against polyQ toxicity. Glucose-6-phosphate dehydrogenase (G6PDH) maintains the reduced form of glutathione (GSH) against oxidative damage, yet it does not contribute to the rpi-knockdown mediated protect from polyQ toxicity. However, I found that knockdown of tansaldolase (tal) can revert back to the defect eye phenotype from the rescued eye by the rpi-knockdown-mediated attenuation of polyQ toxicity. The kncodown of rpi reduces the levels of phosphorylated S6K and 4EBP which are the downstream target proteins of TOR pathway. In sum, the knockdown of rpi on the rescued fly eye from polyQ toxicity may also depend on apoptosis, autophagy, and TOR pathways.

關鍵字

果蠅 ； 多麩醯胺酸蛋白

參考文獻

Aladzsity, I., Toth, M.L., Sigmond, T., Szabo, E., Bicsak, B., Barna, J., Regos, A., Orosz, L., Kovacs, A.L., and Vellai, T. (2007). Autophagy genes unc-51 and bec-1 are required for normal cell size in Caenorhabditis elegans. Genetics 177, 655-660.

Bae, B.I., Xu, H., Igarashi, S., Fujimuro, M., Agrawal, N., Taya, Y., Hayward, S.D., Moran, T.H., Montell, C., Ross, C.A., et al. (2005). p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron 47, 29-41.

Banki, K., Hutter, E., Colombo, E., Gonchoroff, N.J., and Perl, A. (1996). Glutathione levels and sensitivity to apoptosis are regulated by changes in transaldolase expression. J Biol Chem 271, 32994-33001.

Beal, M.F. (2005). Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58, 495-505.

Blommaart, E.F., Luiken, J.J., Blommaart, P.J., van Woerkom, G.M., and Meijer, A.J. (1995). Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 270, 2320-2326.