請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40272完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 符文美 | |
| dc.contributor.author | Yi-Ling Chang | en |
| dc.contributor.author | 張依琳 | zh_TW |
| dc.date.accessioned | 2021-06-14T16:43:47Z | - |
| dc.date.available | 2008-09-11 | |
| dc.date.copyright | 2008-09-11 | |
| dc.date.issued | 2008 | |
| dc.date.submitted | 2008-07-30 | |
| dc.identifier.citation | Beal, M. F. (2003) Bioenergetic approaches for neuroprotection in Parkinson's disease. Ann Neurol, 53 Suppl 3, S39-47; discussion S47-38.
Beilina, A., Van Der Brug, M., Ahmad, R., Kesavapany, S., Miller, D. W., Petsko, G. A. and Cookson, M. R. (2005) Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci U S A, 102, 5703-5708. Betarbet, R., Sherer, T. B. and Greenamyre, J. T. (2002) Animal models of Parkinson's disease. Bioessays, 24, 308-318. Bogaerts, V., Theuns, J. and van Broeckhoven, C. (2008) Genetic findings in Parkinson's disease and translation into treatment: a leading role for mitochondria? Genes Brain Behav, 7, 129-151. Bonifati, V., Rohe, C. F., Breedveld, G. J. et al. (2005) Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology, 65, 87-95. Bove, J., Prou, D., Perier, C. and Przedborski, S. (2005) Toxin-induced models of Parkinson's disease. NeuroRx, 2, 484-494. Chandra, J., Samali, A. and Orrenius, S. (2000) Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med, 29, 323-333. Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J. R., Seol, J. H., Yoo, S. J., Hay, B. A. and Guo, M. (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature, 441, 1162-1166. Criscuolo, C., Volpe, G., De Rosa, A. et al. (2006) PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of parkinsonism. Mov Disord, 21, 1265-1267. Damier, P., Hirsch, E. C., Zhang, P., Agid, Y. and Javoy-Agid, F. (1993) Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience, 52, 1-6. Deng, H., Jankovic, J., Guo, Y., Xie, W. and Le, W. (2005a) Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem Biophys Res Commun, 337, 1133-1138. Deng, H., Le, W. D., Zhang, X., Pan, T. H. and Jankovic, J. (2005b) G309D and W437OPA PINK1 mutations in Caucasian Parkinson's disease patients. Acta Neurol Scand, 111, 351-352. Eberhardt, O., Coelln, R. V., Kugler, S. et al. (2000) Protection by synergistic effects of adenovirus-mediated X-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. J Neurosci, 20, 9126-9134. Forno, L. S., DeLanney, L. E., Irwin, I., Di Monte, D. and Langston, J. W. (1992) Astrocytes and Parkinson's disease. Prog Brain Res, 94, 429-436. Gandhi, S., Muqit, M. M., Stanyer, L. et al. (2006) PINK1 protein in normal human brain and Parkinson's disease. Brain, 129, 1720-1731. Gash, D. M., Zhang, Z., Ovadia, A. et al. (1996) Functional recovery in parkinsonian monkeys treated with GDNF. Nature, 380, 252-255. Halliwell, B. (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem, 97, 1634-1658. Haque, M. E., Thomas, K. J., D'Souza, C. et al. (2008) Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc Natl Acad Sci U S A, 105, 1716-1721. Hatano, Y., Li, Y., Sato, K. et al. (2004) Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol, 56, 424-427. Hedrich, K., Hagenah, J., Djarmati, A. et al. (2006) Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit? Arch Neurol, 63, 833-838. Henze, C., Hartmann, A., Lescot, T., Hirsch, E. C. and Michel, P. P. (2005) Proliferation of microglial cells induced by 1-methyl-4-phenylpyridinium in mesencephalic cultures results from an astrocyte-dependent mechanism: role of granulocyte macrophage colony-stimulating factor. J Neurochem, 95, 1069-1077. Hirsch, E. C., Hunot, S., Damier, P. et al. (1999) Glial cell participation in the degeneration of dopaminergic neurons in Parkinson's disease. Adv Neurol, 80, 9-18. Hughes, A. J., Daniel, S. E., Blankson, S. and Lees, A. J. (1993) A clinicopathologic study of 100 cases of Parkinson's disease. Arch Neurol, 50, 140-148. Inazu, M., Takeda, H. and Matsumiya, T. (2003) [The role of glial monoamine transporters in the central nervous system]. Nihon Shinkei Seishin Yakurigaku Zasshi, 23, 171-178. John, G. R., Lee, S. C. and Brosnan, C. F. (2003) Cytokines: powerful regulators of glial cell activation. Neuroscientist, 9, 10-22. Keeney, P. M., Xie, J., Capaldi, R. A. and Bennett, J. P., Jr. (2006) Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci, 26, 5256-5264. Kitada, T., Pisani, A., Porter, D. R. et al. (2007) Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A, 104, 11441-11446. Klein, C. and Lohmann-Hedrich, K. (2007) Impact of recent genetic findings in Parkinson's disease. Curr Opin Neurol, 20, 453-464. Kordower, J. H., Emborg, M. E., Bloch, J. et al. (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science, 290, 767-773. Lang, A. E. and Lozano, A. M. (1998) Parkinson's disease. Second of two parts. N Engl J Med, 339, 1130-1143. Mizuno, Y., Ohta, S., Tanaka, M., Takamiya, S., Suzuki, K., Sato, T., Oya, H., Ozawa, T. and Kagawa, Y. (1989) Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. Biochem Biophys Res Commun, 163, 1450-1455. Murakami, T., Moriwaki, Y., Kawarabayashi, T. et al. (2007) PINK1, a gene product of PARK6, accumulates in alpha-synucleinopathy brains. J Neurol Neurosurg Psychiatry, 78, 653-654. Park, J., Lee, S. B., Lee, S. et al. (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature, 441, 1157-1161. Perier, C., Tieu, K., Guegan, C. et al. (2005) Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage. Proc Natl Acad Sci U S A, 102, 19126-19131. Petit, A., Kawarai, T., Paitel, E. et al. (2005) Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem, 280, 34025-34032. Pridgeon, J. W., Olzmann, J. A., Chin, L. S. and Li, L. (2007) PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1. PLoS Biol, 5, e172. Raha, S. and Robinson, B. H. (2000) Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci, 25, 502-508. Rhee, S. G. (2006) Cell signaling. H2O2, a necessary evil for cell signaling. Science, 312, 1882-1883. Rohe, C. F., Montagna, P., Breedveld, G., Cortelli, P., Oostra, B. A. and Bonifati, V. (2004) Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism. Ann Neurol, 56, 427-431. Schapira, A. H. (2008) Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol, 7, 97-109. Schapira, A. H., Cooper, J. M., Dexter, D., Jenner, P., Clark, J. B. and Marsden, C. D. (1989) Mitochondrial complex I deficiency in Parkinson's disease. Lancet, 1, 1269. Sim, C. H., Lio, D. S., Mok, S. S., Masters, C. L., Hill, A. F., Culvenor, J. G. and Cheng, H. C. (2006) C-terminal truncation and Parkinson's disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Hum Mol Genet, 15, 3251-3262. Sortwell, C. E., Daley, B. F., Pitzer, M. R., McGuire, S. O., Sladek, J. R., Jr. and Collier, T. J. (2000) Oligodendrocyte-type 2 astrocyte-derived trophic factors increase survival of developing dopamine neurons through the inhibition of apoptotic cell death. J Comp Neurol, 426, 143-153. Stone, J. R. and Yang, S. (2006) Hydrogen peroxide: a signaling messenger. Antioxid Redox Signal, 8, 243-270. Tang, B., Xiong, H., Sun, P. et al. (2006) Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. Hum Mol Genet, 15, 1816-1825. Teismann, P., Tieu, K., Cohen, O., Choi, D. K., Wu, D. C., Marks, D., Vila, M., Jackson-Lewis, V. and Przedborski, S. (2003) Pathogenic role of glial cells in Parkinson's disease. Mov Disord, 18, 121-129. Tipton, K. F. and Singer, T. P. (1993) Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J Neurochem, 61, 1191-1206. Tripanichkul, W., Sripanichkulchai, K. and Finkelstein, D. I. (2006) Estrogen down-regulates glial activation in male mice following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication. Brain Res, 1084, 28-37. Turrens, J. F. (2003) Mitochondrial formation of reactive oxygen species. J Physiol, 552, 335-344. Valente, E. M., Abou-Sleiman, P. M., Caputo, V. et al. (2004a) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science, 304, 1158-1160. Valente, E. M., Salvi, S., Ialongo, T. et al. (2004b) PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol, 56, 336-341. Verity, A. N., Wyatt, T. L., Hajos, B., Eglen, R. M., Baecker, P. A. and Johnson, R. M. (1998) Regulation of glial cell line-derived neurotrophic factor release from rat C6 glioblastoma cells. J Neurochem, 70, 531-539. Wang, D., Qian, L., Xiong, H. et al. (2006) Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc Natl Acad Sci U S A, 103, 13520-13525. Yang, Y., Gehrke, S., Imai, Y. et al. (2006) Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci U S A, 103, 10793-10798. Zadikoff, C., Rogaeva, E., Djarmati, A., Sato, C., Salehi-Rad, S., St George-Hyslop, P., Klein, C. and Lang, A. E. (2006) Homozygous and heterozygous PINK1 mutations: considerations for diagnosis and care of Parkinson's disease patients. Mov Disord, 21, 875-879. Zhang, S., Zhou, F., Ding, J. H., Zhou, X. Q., Sun, X. L. and Hu, G. (2007) ATP-sensitive potassium channel opener iptakalim protects against MPP-induced astrocytic apoptosis via mitochondria and mitogen-activated protein kinase signal pathways. J Neurochem, 103, 569-579. Zhou, H., Falkenburger, B. H., Schulz, J. B., Tieu, K., Xu, Z. and Xia, X. G. (2007) Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice. Int J Biol Sci, 3, 242-250. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40272 | - |
| dc.description.abstract | 巴金森氏症是很常見的神經退化性疾病之一，病人在黑質組織的多巴胺神經元有退化的情形，但對於其致病之分子機制尚未明確。PINK1是造成隱性遺傳巴金森氏症第二普遍的基因，在神經細胞，PINK1似乎可以保護細胞免於氧化壓力造成的死亡。神經膠質細胞在調控腦內環境的平衡及對神經的存活上扮演了重要角色，所以在本篇論文，我們利用人類星狀細胞瘤之細胞株A172，將PINK1 knockdown或轉殖PINK1 mutant到細胞，來探討PINK1在星狀細胞之作用。實驗結果顯示，將PINK1 knockdown後，給予H2O2，粒線體膜電位降低會加劇、可以促進細胞內ROS的產生，並且伴隨著MTT測得的存活率降低；若細胞轉殖PINK1 mutant (G309D或K219A) 再給予H2O2後，也會看到MTT測得的存活率降低。而且H2O2造成的死亡並不是因為星狀細胞分泌GDNF減少的關係。另外，給予MPP+也造成PINK1 knockdown後ROS的產生增加。所以PINK1對於星狀細胞在氧化壓力之情況下有保護的功能。 | zh_TW |
| dc.description.abstract | Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, characterized by the selective and progressive loss of dopaminergic neurons in the substantia nigra. The pathogenic mechanism of PD is still unclear. Mutations in the human, PTEN-induced putative kinase 1 (PINK1) is the second most common causative gene of recessive familial PD. PINK1 protein was proved to be protective for oxidative stress and neuronal apoptosis. Glial cells play an important role in the homeostasis of the microenvironment which is supportive for the survival of neurons. Up to date, the function of the PINK1 protein in the glial cells has not been studied yet. To address this issue, we used human astrocytoma cell line (A172) and transfected PINK1 shRNA and PINK1 mutnats mimicking the reduced expression of functional PINK1 protein. Silencing the expression of PINK1 protein potentiated the H2O2–induced reduction of mitochondria membrane potential, and also enhanced H2O2 and MPP+-induced increase of ROS production. Furthermore, while analyzed using MTT assay, decrease of the cell viability following exposure to H2O2 was observed in the PINK1 shRNA transfected astrocytoma cells. PINK1 mutant (G309D or K219A) also decreased the cell viability following exposure to H2O2. Glial cell derived nerve growth factor (GDNF) which is important in nourishing the neurons, was not reduced in those glial cells with reduced expression of PINK1. Our results show that PINK1 can prevent astrocytes from oxidative stress and cell death. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-14T16:43:47Z (GMT). No. of bitstreams: 1 ntu-97-R95443018-1.pdf: 1337328 bytes, checksum: e385fc22fe8ae0b3a26c2b9e73e1c764 (MD5) Previous issue date: 2008 | en |
| dc.description.tableofcontents | 誌謝............................................................................................................I
中文摘要………………………………………………………………...II 英文摘要………………………………………………………………..III 縮寫表……………………………………………………………………1 第一章 緒論..……………………………………………………………3 1.1 巴金森氏症……………………………………………………...3 1.2 PINK1……………………………………………………………5 1.3 粒線體及氧化壓力……………………………………………...7 1.4 星狀細胞………………………………………………………...8 第二章 實驗材料與方法………………………………………………16 2.1 實驗材料……………………………………………………….16 2.2 實驗方法……………………………………………………….17 第三章 結果……………………………………………………………23 3.1 利用PINK1 shRNA可減少A172的PINK1蛋白之表現…...23 3.2 H2O2及MPP+會降低A172的粒線體膜電位………………….23 3.3 PINK1 knockdown會使H2O2造成A172粒線體膜電位的降低加劇……………………………………………………………..25 3.4 PINK1 knockdown對MPP+造成A172粒線體膜電位降低的影響………………………………………………………………..26 3.5 H2O2及MPP+會增加A172的活性氧產生量…………………27 3.6 PINK1 knockdown會加劇H2O2造成A172的活性氧增加…..27 3.7 PINK1 knockdown對MPP+造成A172活性氧增加的影響….28 3.8 H2O2、MPP+及6-OHDA會減少A172的存活率…………….29 3.9 PINK1 knockdown會促進H2O2造成A172凋化的速率……..30 3.10 PINK1 knockdown對MPP+造成A172存活率降低的影響…31 3.11 PINK1 knockdown對6-OHDA造成A172存活率降低的影響………………………………………………………………31 3.12 H2O2會增加A172的GDNF mRNA之表現…………………32 3.13 PINK1 knockdown對H2O2增加A172 GDNF mRNA表現的影響………………………………………………………………32 3.14 將PINK1 mutant大量表現會使A172的PINK1 mRNA表現增加……………………………………………………………33 3.15 PINK1 mutant對H2O2造成A172 外觀形態的影響………..34 3.16 PINK1 mutant會使H2O2造成A172存活率的降低加劇……34 3.17 PINK1 mutant對H2O2增加A172 GDNF mRNA表現的影 響………………………………………………………………35 第四章 討論............……………………………………………………36 圖表……………………………………………………………………..42 參考文獻………………………………………………………………..59 圖目錄 附圖一…………………………………………………………………..12 附圖二…………………………………………………………………..13 附圖三 Mitochondrial structure and composition of the mitochondrial respiratory chain………………………………………….……14 附圖四 ROS……………………………………………………………15 Figure 1. Knockdown of PINK1 protein expression by PINK1 shRNA in A172 cells…………………………………………………….42 Figure 2. Decrease of mitochondria membrane potential by H2O2 or MPP+ in A172 cells………………………………………………….43 Figure 3. Enhancement of H2O2-induced reduction of mitochondria membrane potential by PINK1 knockdown in A172 cells…...44 Figure 4. Effect of PINK1 shRNA on the mitochondria membrane potential in A172 cells exposed to MPP+…………………….45 Figure 5. Increase of reactive oxygen species (ROS) by H2O2 or MPP+ in A172 cells…………………………………………………….46 Figure 6. Increase of H2O2-induced reactive oxygen species (ROS) production by PINK1 knockdown in A172 cells……………..47 Figure 7. Effect of PINK1 knockdown on the MPP+-induced reactive oxygen species (ROS) production in A172 cells……………..48 Figure 8. Decrease of cell viability by H2O2, MPP+ or 6-OHDA in A172 cells…………………………………………………………...49 Figure 9. Decrease of cell viability by PINK1 Knockdown in A172 cells exposed to H2O2………………………………………..……50 Figure 10. Lack of effect of PINK1 knockdown on the cell viability in A172 cells exposed to MPP+……………………………..…51 Figure 11. Lack of effect of PINK1 knockdown on the cell viability in A172 cells exposed to 6-OHDA…………………………….52 Figure 12. Increase of GDNF mRNA expression by H2O2 in A172 cells………………………………………………………….53 Figure 13. Lack of Effect of PINK1 knockdown on the H2O2-induced increase of GDNF mRNA expression in A172 cells………..54 Figure 14. Overexpression of PINK1 mutant enhanced PINK1 mRNA expression in A172 cells………………………………….…55 Figure 15. Effect of PINK1 mutant on the morphological change in A172 cells exposed to H2O2…………………………………….…56 Figure 16. Decrease of cell viability by PINK1 mutant in A172 cells exposed to H2O2………………………………………….…57 Figure 17. Lack of Effect of PINK1 mutant on the H2O2-induced increase of GDNF mRNA expression in A172 cells………………....58 | |
| dc.language.iso | zh-TW | |
| dc.subject | PTEN-induced putative kinase 1 (PINK1) | zh_TW |
| dc.subject | 星狀細胞 | zh_TW |
| dc.subject | 氧化壓力 | zh_TW |
| dc.subject | 巴金森氏症 | zh_TW |
| dc.subject | PTEN-induced putative kinase 1 (PINK1) | en |
| dc.subject | astrocytes | en |
| dc.subject | oxidative stress | en |
| dc.title | 巴金森氏症致病基因PINK1變異在人類星狀細胞作用之探討 | zh_TW |
| dc.title | Effect of Parkinson-related PINK1 defect on human astrocytes | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 96-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李銘仁,劉宏輝,王家儀,楊春茂 | |
| dc.subject.keyword | 星狀細胞,氧化壓力,巴金森氏症,PTEN-induced putative kinase 1 (PINK1), | zh_TW |
| dc.subject.keyword | astrocytes,oxidative stress,PTEN-induced putative kinase 1 (PINK1), | en |
| dc.relation.page | 64 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2008-08-01 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-97-1.pdf 未授權公開取用 | 1.31 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。