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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳韻如(Yun-Ru Chen) | |
| dc.contributor.author | Shu-Ting Cai | en |
| dc.contributor.author | 蔡叔庭 | zh_TW |
| dc.date.accessioned | 2023-03-19T23:27:30Z | - |
| dc.date.copyright | 2022-10-19 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-09-23 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/85881 | - |
| dc.description.abstract | 醣化修飾為細胞中最主要的轉譯後修飾，其中將六碳胺基糖生化合成代謝的最終產物胺基糖，經由胺基糖轉移酶催化至蛋白質上絲氨酸或是蘇胺酸位點的醣基化修飾，在細胞中只由一對酵素胺基糖轉移酶和胺基糖分解酶控制整個胺基糖轉譯後修飾，此種修飾通常與蛋白質穩定性、蛋白質分布和蛋白質酵素活性的調節相關。在大腦組織中有許多酵素已知受到胺基糖轉譯後修飾調節，且在阿茲海默症病人的腦組織中發現胺基糖修飾大幅下降。在大腦中主要表現的類型一六碳糖激酶(HK1)分布在粒線體外膜上，參與糖解作用的關鍵步驟將六碳糖催化為磷酸化六碳糖，此一步驟也存在六碳胺基糖生化合成代謝中，和調節細胞中胺基糖水平相關。前人研究當中亦發現當六碳糖激酶(HK1)和粒線體結合能力下降，將會誘發細胞凋亡反應。根據過去實驗室成員的研究成果，已知六碳糖激酶(HK1)存在胺基糖轉譯後修飾，但此修飾對六碳糖胺基糖的生化功能有何影響，仍需進一步探究，為此在本篇研究當中，藉由調整細胞內整體胺基糖水平，在不同水平下觀察六碳糖激酶蛋白質生化功能有何變化。結果發現利用基因方法下降人類神經母腫瘤細胞內的胺基糖轉移酶表現以達到下調細胞胺基糖水平，在此背景下發現六碳糖激酶(HK1)的蛋白質穩定性並不受影響。但上調人類胚胎腎細胞的胺基糖水平卻能夠增加六碳糖激酶(HK1)和粒線體外膜的結合能力，反之下調其胺基糖水平，則能觀測到六碳糖激酶(HK1)和粒線體外膜的結合能力下降。另外，不管在下降或是上調胺基糖水平的背景下測試六碳糖激酶的酵素催化活性並無顯著差異性。由上述結果可以得知細胞內胺基糖轉譯後修飾水平會影響到六碳糖激酶(HK1)細胞內分布定位，但不會影響其蛋白質穩定性以及其酵素催化活性。另外在其他已發表的論文中提到在阿茲海默症的病理模型中，觀察到類澱粉蛋白質(Aβ)大量堆積，並且影響到六碳糖激酶(HK1)與粒線體外膜結合能力，結合本研究內容，我們在人類神經母腫瘤細胞中處理乙型類澱粉蛋白，以觀察其對六碳糖激酶的胺基糖轉譯後修飾或是其他蛋白質生化功能有何影響，在此種背景下進一步探究其在阿茲海默症的病理意義。 | zh_TW |
| dc.description.abstract | Glycosylation is considered to be a major post-translational modification. O-GlcNAcylation refers to the addition of N-acetylglucosamine, the end product of Hexosamine Biosynthetic Pathway (HBP), on serine or threonine residues of cytosolic or nuclear proteins through the catalysis by O-GlcNAc transferase (OGT). O-GlcNAc modification is often associated with protein stability, enzyme activity, and subcellular localization. The whole O-GlcNAcylation on proteins is only controlled by O-GlcNAc transferase and O-GlcNAcase in cells. There are many enzymes in brain regulated by O-GlcNAcylation where abnormal O-GlcNAc level has been found in Alzheimer’s disease (AD). Hexokinase 1 (HK1), the brain isoform of hexokinase, is localized at the mitochondria outer membrane. HK1 is the key enzyme in the first step of glycolysis and HBP. It was shown that the detachment of HK1 from mitochondria may cause apoptosis. Previously, we identified HK-1 is O-GlcNAcylated, but the O-GlcNAc effect and sites remains unknown. In this study, using genetic, pharmacological, imaging, and biochemical approaches, I demonstrated that knockdown O-GlcNAc transferase (OGT) in human neuroblastoma BE(2)-C cells caused O-GlcNAc level reduction, but not the protein stability of HK1. Overexpressing OGT in HEK293 cells increased the level of mitochondrial HK1 and the colocalization of HK1 on mitochondria. On the other hand, knockdown OGT in HEK293 cells reduced HK1 level in mitochondrial fraction. As for the enzyme activity of HK1, neither the OGT knockdown group nor OGT overexpression shows a significant difference comparing to the control. These results suggest that the O-GlcNAc level affects the subcellular localization of HK1 but not its stability or enzyme activity in cells. Moreover, some references mentioned that Amyloid-β (Aβ), the pathological hallmark in AD, affects HK1 function. Therefore, I conducted Aβ treatment in BE(2)-C cells to examine the effects on HK1 O-GlcNAylation and function. Together, I provided the effect of O-GlcNAcylation on HK1 and will further investigate the related mechanism in AD. | en |
| dc.description.provenance | Made available in DSpace on 2023-03-19T23:27:30Z (GMT). No. of bitstreams: 1 U0001-2009202215531000.pdf: 4238775 bytes, checksum: 39e77373fb7d17ca6cea595e3529f0c4 (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | Contents 中文摘要 i Abstract iii 致謝 v Chapter 1 Introduction 1 1.1 Post-translational modification 1 1.2 Glycosylation 1 1.3 O-GlcNAcylation 2 1.3.1 Overview 2 1.3.2 O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) 2 1.4 Hexokinase 3 1.4.1 The role of hexokinase 3 1.4.2 Hexokinase 1 is located at the mitochondrial outer membrane 4 1.5 Alzheimer's disease 5 1.5.1 Abnormal accumulation of misfolded proteins is characterized in AD 5 1.5.2 The role of O-GlcNAcylation in AD pathology 6 1.5.3 Aβ-induced cellular redistribution of HK1 plays a role in AD 6 Research aims 7 Chapter 2 Methods 9 2.1 Method 9 2.1.1 Plasmid construction, cell culture and plasmid transfection 9 2.1.2 Cycloheximide (CHX) chase assay for protein stability 10 2.1.3 Mitochondrial and cytosol fraction fractionation 10 2.1.4 Immunoprecipitation 11 2.1.5 Western blotting 11 2.1.6 Protein digestion and LC-MS/MS analysis 12 2.1.7 Aβ40 or Aβ42 fibril formation and treatment 12 2.1.8 High content cell image analysis by Model-MD ImageXpress Micro 13 2.1.9 Seahorse analysis 14 2.1.10 Hexokinase enzyme activity 15 2.1.11 O-GlcNAcylated HK1-His protein expression and purification 16 Chapter 3 Results 17 3.1 Transient transfections in mammalian cells 17 3.1.1 Knockdown or overexpression of OGT in HEK293 cells 17 3.1.2 Knockdown or overexpression of OGT in BE(2)-C cells 18 3.2 Protein stability 18 3.2.1 The effect of O-GlcNAcylation on HK1 protein stability in cells 18 3.3 Subcellular localization 19 3.3.1 The effect of O-GlcNAcylation on the distribution of HK1 in HEK293 19 3.3.2 The effect of O-GlcNAcylation on the distribution of HK1 in BE(2)-C 20 3.3.3 The overall mitochondrial HK1 level in cells 20 3.4 Enzyme activity 21 3.5 The altered ability of subcellular localization on HK1 potentially involved in defective mitochondria function 22 3.5.1 The measurement of mitochondria stress by seahorse analysis 22 3.5.2 The measurement of glycolysis stress by seahorse analysis 23 3.5.3 The measurement of ATP level by seahorse analysis 24 3.6 Aβ fibril treatment in BE(2)-C cells 25 3.7 Mapping O-GlcNAc site on HK1 peptide 26 3.8 O-GlcNAcylated HK1 protein purification 26 Chapter 4 Discussion 27 Figures 32 Figure 1. The protein expression level under knockdown OGT in HEK293 cells. 32 Figure 2. The O-GlcNAcylation level and protein expression level under OGT overexpression in HEK293 cells. 33 Figures 3. The protein expression level under knockdown OGT in BE(2)-C cells. 35 Figures 4. The protein expression level under OGT overexpression in BE(2)-C cells. 36 Figures 5. Protein stability of Flag-HK1 in HEK293 cells. 37 Figures 6. Protein stability of HK1 in BE(2)-C cells. 38 Figures 7. The co-localization images of Flag-HK1 and mitochondria in HEK293 cells. 39 Figures 8. The co-localization analysis of Flag-HK1 and mitochondria in HEK293 cells. 40 Figures 9. Mitochondrial HK1 level in OGT knockdown groups in HEK293 cells. 41 Figures 10. Mitochondrial HK1 level in OGT overexpression group in HEK293 cells. 42 Figures 11. The co-localization images of HK1 and mitochondria in BE(2)-C cells. 43 Figures 12. The co-localization analysis of HK1 and mitochondria in BE(2)-C cells. 44 Figures 13. Mitochondrial HK1 level in OGT knockdown groups in BE(2)-C cells 45 Figures 14. Mitochondrial HK1 level in OGT overexpression groups in BE(2)-C cells. 46 Figure 15. The enzyme activity of hexokinase in cells. 47 Figure 16. FCCP titration test in HEK293 and BE(2)-C cells. 48 Figure 17. Mitochondrial stress detection in the OGT knockdown group by seahorse analysis in HEK293 cells. 49 Figure 18. Mitochondrial stress detection in OGT overexpression group by seahorse analysis in HEK293 cells. 50 Figure 19. Mitochondrial stress detection in OGT knockdown group by seahorse analysis in BE(2)-C cells. 51 Figure 20. Mitochondrial stress detection in OGT overexpression group by seahorse analysis in BE(2)-C cells. 52 Figure 21. Glycolysis stress detection by seahorse analysis in HEK293 cells. 53 Figure 22. Glycolysis stress detection by seahorse analysis in BE(2)-C cell. 54 Figure 23. Total ATP production in BE(2)-C cells. 55 Figure 24. Aβ40 or 42 fibril treatments in BE(2)-C cells. 56 Figure 25. Aβ40 or 42 fibril treatments in BE(2)-C cells(IP). 57 Figure 26. The map of pEGFP-N3-HK1. 58 Figure 27. The map of pET28a-hHK1-His. 59 Figure 28. Protein purification of HK1-His from BL21 cell lysates by FPLC 60 References 62 附錄一 : Materials 67 | |
| dc.language.iso | en | |
| dc.subject | 胺基糖糖化修飾 | zh_TW |
| dc.subject | 醣化修飾 | zh_TW |
| dc.subject | 己糖磷酸酶 | zh_TW |
| dc.subject | 粒線體能量代謝反應代謝反應 | zh_TW |
| dc.subject | 類澱粉蛋白 | zh_TW |
| dc.subject | 胺基糖轉移酶 | zh_TW |
| dc.subject | 亞細胞定位分布 | zh_TW |
| dc.subject | O-GlcNAc transferase | en |
| dc.subject | O-GlcNAcylation | en |
| dc.subject | Glycosylation | en |
| dc.subject | subcellular localization | en |
| dc.subject | mitochondrial metabolism | en |
| dc.subject | Amyloid-β | en |
| dc.subject | Hexokinase 1 | en |
| dc.title | 探討O連結乙醯葡萄氨糖修飾對於六碳糖激酶的影響以及在阿茲海默症中扮演的角色 | zh_TW |
| dc.title | Investigation of O-GlcNAcylation on hexokinase 1 in Alzheimer’s disease | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 廖憶純(Yi-Chun Liao),鄭梅君(Mei-Chun Cheng) | |
| dc.subject.keyword | 醣化修飾,胺基糖糖化修飾,己糖磷酸酶,粒線體能量代謝反應代謝反應,類澱粉蛋白,胺基糖轉移酶,亞細胞定位分布, | zh_TW |
| dc.subject.keyword | Glycosylation,O-GlcNAcylation,Hexokinase 1,mitochondrial metabolism,Amyloid-β,O-GlcNAc transferase,subcellular localization, | en |
| dc.relation.page | 75 | |
| dc.identifier.doi | 10.6342/NTU202203656 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2022-09-25 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| dc.date.embargo-lift | 2027-10-01 | - |
| 顯示於系所單位： | 生化科技學系 | |
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