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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92322完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳韻如 | zh_TW |
| dc.contributor.advisor | Yun-Ru Chen | en |
| dc.contributor.author | 張育仁 | zh_TW |
| dc.contributor.author | Yu-Jen Chang | en |
| dc.date.accessioned | 2024-03-21T16:36:50Z | - |
| dc.date.available | 2024-03-23 | - |
| dc.date.copyright | 2024-03-21 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-02-18 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92322 | - |
| dc.description.abstract | 額顳葉失智症(frontotemporal lobar dementia, FTLD)和肌萎縮側索硬化症(amyotrophic lateral sclerosis, ALS)中最常見的突變是C9ORF72基因非編碼區域中的六核苷酸GGGGCC (簡稱G4C2)的重複擴增。FTLD是一種具有額顳葉型神經退化、行為能力缺陷和逐漸產生失語症為特徵的神經退化性疾病。而ALS則是一種上下運動神經元兩者皆受影響的運動神經元疾病，ALS惡化極為快速，確診後病人平均剩下二至五年的壽命。而這兩種看似差異極大的疾病卻擁有相當多共同的病理特徵和基因突變。
與C9ORF72突變相關的病理機制包括C9ORF72蛋白質功能的喪失和涉及RNA和蛋白質增益毒性。由於核苷酸重複所導致非ATG啟動的蛋白質轉譯機制(RAN)作用，在C9ORF72的六核苷酸重複擴增可以產生五種雙胜肽重複，包括了聚甘胺酸-丙胺酸、聚甘胺酸-精胺酸、聚甘胺酸-脯胺酸、聚脯胺酸-精胺酸和聚脯胺酸-丙胺酸。這些雙胜肽重複序列可源自於正義和反義RNA，而在FTLD或ALS患者的海馬迴、額葉和運動皮質層、脊髓和小腦中，都可鑑定出這些雙胜肽重複序列。 在這些雙胜肽重複序列中，聚甘胺酸-精胺酸和聚脯胺酸-精胺酸，這兩種富含精胺酸的雙胜肽重複序列，被認為是最具毒性的兩種。關於聚甘胺酸-精胺酸和聚脯胺酸-精胺酸的毒性機制目前仍在積極研究中。提出的機制包括引起核仁壓力、阻塞核仁孔的運輸、破壞核糖體與RNA的合成、降低粒線體功能和抑制蛋白質轉譯。雖然所有雙胜肽重複序列都可在細胞質包含體中觀察到，但聚甘胺酸-丙胺酸含量是最豐富的，並且可以錯誤堆積成具神經毒性的類澱粉沉積物。此外，聚甘胺酸-丙胺酸被認為會影響蛋白酶體的功能並誘導另一病理蛋白TDP-43的錯誤定位和聚集。另一方面，目前沒有文獻指出聚甘胺酸-脯胺酸和聚脯胺酸-丙胺酸具有毒性。 在正常人基因中的G4C2重複次數從2到24次皆有可能，而在ALS患者中，它的範圍則從30擴增至數百甚至上千次不等。關於精確會造成病理現象以及產生雙胜肽重複胜肽鏈的G4C2重複次數仍不清楚。在以下這個對聚甘胺酸-精胺酸和聚脯胺酸-精胺酸病理機制進行的研究中，我們使用化學合成的聚甘胺酸-精胺酸和聚脯胺酸-精胺酸來檢驗要產生細胞毒性所需的最小長度。並且利用圓二色譜光譜和小角度X射線散射結合分子模擬，我們提供了聚甘胺酸-精胺酸/聚脯胺酸-精胺酸的可能結構。並且利用脂質體泄漏和鈣流入實驗我們測試了聚甘胺酸-精胺酸和聚脯胺酸-精胺酸對於生物膜的破壞。並且在聚甘胺酸-精胺酸肽鏈中置換多個脯胺酸來進一步檢驗與螺旋構型相關的細胞毒性。我們還使用了等溫量熱法來評估聚甘胺酸-精胺酸/聚脯胺酸-精胺酸與核苷酸的結合與交互作用。此外，我們也進一步研究了聚甘胺酸-精胺酸/聚脯胺酸-精胺酸對DNA複製、RNA轉錄或蛋白質轉譯的抑制以及在細胞中核質運輸的破壞。最後，利用糖分子庫我們篩選出了一種具硫酸化的雙糖可以逆轉上述提到的毒性。利用ALS病人身上取得的多功能幹細胞分化而成的運動神經元，我們發現這個雙糖分子還可以增加此類神經元存活率，並且在聚甘胺酸-精胺酸/聚脯胺酸-精胺酸基因轉殖的果蠅模型上，我們發現這個雙糖分子可以延長其壽命和改善其運動功能。最後，若我們在小鼠腦部運動皮層注射聚甘胺酸-精胺酸會看到其運動功能的退化，利用這個雙糖分子我們亦可以反轉這個現象，為日後藥物的發展找尋契機。 | zh_TW |
| dc.description.abstract | The most prevalent mutation in frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) is the expansion of the hexanucleotide GGGGCC, G4C2, repeat in the non-coding region of the C9ORF72 gene. FTLD is a neurodegenerative disease characterized by frontotemporal dementia, behavioral deficits, and progressive aphasia. ALS, on the other hand, is a motor neuron disease affecting both upper and lower motor neurons, leading to paralysis with an average survival time of two to five years. These two disorders share common pathologies and gene mutations.
The pathological mechanisms associated with the C9ORF72 mutation include both loss of function and gain of function, involving reported RNA and protein toxicity. Repeat-associated non-ATG (RAN) initiated translation generates five dipeptide repeats (DPRs) from the hexanucleotide repeat expansion: poly-glycine-alanine (GA), poly-glycine-arginine (GR), poly-glycine-proline (GP), poly-proline-arginine (PR), and poly-proline-alanine (PA). These DPRs, originating from both sense and antisense RNA, are identified in the hippocampus, frontal and motor cortices, spinal cord, and cerebellum of FTLD or ALS patients. Among the DPRs, poly-GR and poly-PR, which are arginine-rich, have been observed as the most toxic species. The mechanisms of toxicity for poly-GR and poly-PR are still under intensive investigation. Proposed pathways include causing nucleolar stress, blocking nuclear pore transportation, compromising ribosomal RNA biogenesis, reducing mitochondrial function, and inhibiting protein translation. While all DPRs are observed in cytoplasmic inclusions, poly-GA is the most abundant and can fibrillize into neurotoxic amyloids. Additionally, poly-GA impairs proteasome function and induces TDP-43 mis-localization and aggregation. In contrast, the toxicities of poly-GP and poly-PA have not been reported. The G4C2 repeat number for healthy individuals ranges from 2 to 24 repeats, while in patients, it varies from over ~30 to hundreds or even thousands. The precise pathological threshold for G4C2 repeat number and the toxicity boundary regarding peptide length of DPRs remain unclear. In my study investigating the disease mechanism of poly-GR/PR, synthetic poly-GR peptides were utilized to examine the minimal length required for poly-GR toxicity. Structural information of poly-GR/PR was provided through circular dichroism (CD) spectroscopy and small angle X-ray scattering (SAXS) combined with molecular simulation. Membrane integrity was assessed through liposome leakage and calcium influx assays following poly-GR/PR treatment. Helix-related cytotoxicity was further examined by introduction of proline residues into poly-GR peptides. Poly-GR/PR interaction with nucleotides was also assessed using isothermal calorimetry. In addition, interference with DNA replication, RNA transcription, or protein translation was further investigated. Besides, compromised nucleocytoplasmic transportation was examined. Finally, a sulfated disaccharide was identified through chemical library screening and reversed most of the toxicities mentioned above. It also rescued poly-GR/PR-induced cytotoxicity in C9-iPS-derived motor neurons, transgenic poly-GR/PR fly models, and a poly-GR-injected mouse model. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-03-21T16:36:50Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-03-21T16:36:50Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
中文摘要 ii ABSTRACT iv TABLE OF CONTENTS vii LIST OF FIGURES xii ABBREVIATIONS xv CHAPTER 1. INTRODUCTION 1 1.1 ALS 1 1.1.1 Introduction of ALS 1 1.1.2 TAR DNA binding protein, TDP-43 3 1.1.3 Mechanisms 4 1.1.3 Familial mutations 7 1.2 C9ORF72 and dipeptide repeats 8 1.2.1 C9ORF72 8 1.2.2 C9ORF72 in ALS 10 1.2.3 Pathological mechanisms of C9ORF72 mutation 11 1.2.4 Repeat-initiated non-ATG translation, RAN 14 1.2.5 Poly-Glycine-Alanine 15 1.2.6 Arginine-rich dipeptide repeats 16 1.3 R-loop 17 1.4 Motivation and Objectives 18 CHAPTER 2. MATERIALS AND METHODS 20 2.1 Materials 20 2.1.1 Antibodies 20 2.1.2 Buffers 20 2.1.3 Commercial reagents 21 2.2 Methods 28 2.2.1 Peptide synthesis and preparation 28 2.2.2 Cell viability and cytotoxicity assays 28 2.2.3 Plasmid construction 30 2.2.4 Cytotoxicity assessment of NSC34 cells expressing poly-GR 32 2.2.5 Far-UV CD spectroscopy 33 2.2.6 SAXS measurement 34 2.2.7 I-TASSER/Rosetta structure calculations and implementation of SAXS constraint 35 2.2.8 Liposome leakage assay 36 2.2.9 Calcium influx assay 37 2.2.10 Nucleus isolation 39 2.2.11 Cell imaging and immunocytochemistry 40 2.2.12 Immuno-TEM 41 2.2.13 Isothermal titration calorimetry (ITC) 42 2.2.14 DNA-protein complex crosslinking 43 2.2.15 PCR experiments 44 2.2.16 Replication assay 46 2.2.17 Transcription assay 46 2.2.18 RNA labeling and flowcytometry 47 2.2.19 Western blot 49 2.2.20 R-loop staining 49 2.2.21 γH2AX staining 51 2.2.22 Newly synthesized protein labeling 51 2.2.23 Nucleocytoplasmic transport assay 52 2.2.24 Drug screening for rescuing GR30 toxicity 53 2.2.25 Motor neuronal differentiation 54 2.2.26 PI staining and immunostaining of control- and C9-iPSC derived MNs 55 2.2.27 Drosophila climbing and longevity assay 56 2.2.28 Animals 57 2.2.29 Surgical procedures 57 2.2.30 Rotarod task 58 2.2.31 Brain tissue preparation 58 2.2.32 Immunohistochemistry staining 59 2.2.33 Statistics 60 CHAPTER 3. RESULTS 61 Part I. Investigating the length-dependent toxicity and structure of arginine-rich dipeptide repeats 61 3.1 Poly-GR toxicity is dose- and length-dependent 61 3.2 Loose helical conformation formed in poly-GR peptides with a length-dependent manner 67 3.3 Proline-introduction reduces helix formation of poly-GR and toxicity induced by helical conformation 72 3.4 Poly-GR/PR peptides differentially disrupt liposomes and plasma/nuclear membranes and poly-GR performed the disruption in a length-dependent manner 76 3.5 Poly-GR possesses stronger binding affinity to DNA than RNA 86 3.6 Poly-GR/PR peptides inhibit replication and transcription 92 3.7 Poly-GR/PR blocks nucleocytoplasmic transport at later stage 105 Part II. Screening potential drugs for C9-ALS 109 3.8 Negatively charged disaccharides rescue cytotoxicity of GR30 109 3.9 A fully sulfated disaccharide, sodium sucrose octasulfate, rescues membrane penetration and transcription inhibition induced by poly-GRs 118 3.10 SOS rescues neuronal toxicity in iPSC-derived MNs from a C9-ALS patient 127 3.11 SOS prolongs the lifespan of Drosophila expressing poly-GR and poly-PR with longer repeat numbers 132 3.12 SOS rescues GR30-induced toxicity in a GR30-injected mouse model 135 CHAPTER 4. DISCUSSION 139 4.1 Investigating the length-dependence of argnine-rich DPRs 139 4.2 Examining structural features and membrane penetration of arginine-rich DPRs 142 4.3 Examining nucleic acids-related toxicity of arginine-rich DPRs 145 4.4 Drug development for C9-ALS 150 REFERENCES 154 | - |
| dc.language.iso | en | - |
| dc.subject | 硫酸化雙糖 | zh_TW |
| dc.subject | 螺旋 | zh_TW |
| dc.subject | 聚脯胺酸-精胺酸 | zh_TW |
| dc.subject | 聚甘胺酸-精胺酸 | zh_TW |
| dc.subject | 膜穿透性 | zh_TW |
| dc.subject | 六核苷酸重複擴增 | zh_TW |
| dc.subject | 肌萎縮側索硬化症 | zh_TW |
| dc.subject | C9ORF72 | zh_TW |
| dc.subject | 二胜肽重複序列 | zh_TW |
| dc.subject | poly-glycine-arginine (poly-GR) | en |
| dc.subject | amyotrophic lateral sclerosis (ALS) | en |
| dc.subject | C9ORF72 | en |
| dc.subject | hexanucleotide repeat expansion | en |
| dc.subject | dipeptide repeats | en |
| dc.subject | poly-proline-arginine (poly-PR) | en |
| dc.subject | helix | en |
| dc.subject | membrane penetration | en |
| dc.subject | sulfated disaccharide | en |
| dc.title | 研究漸凍人症中富含精胺酸之二胜肽重複序列的毒理機制以及潛在的治療藥物 | zh_TW |
| dc.title | Investigating toxicity mechanisms and potential therapeutics of arginine-rich dipeptide repeats in amyotrophic lateral sclerosis (ALS) | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.coadvisor | 潘建源 | zh_TW |
| dc.contributor.coadvisor | Chien-Yuan Pan | en |
| dc.contributor.oralexamcommittee | 姚季光;鄭有舜;高承福 | zh_TW |
| dc.contributor.oralexamcommittee | Chi-Kuang Yao;U-Ser Jeng;Cheng-Fu Kao | en |
| dc.subject.keyword | 肌萎縮側索硬化症,六核苷酸重複擴增,二胜肽重複序列,聚甘胺酸-精胺酸,聚脯胺酸-精胺酸,螺旋,膜穿透性,硫酸化雙糖,C9ORF72, | zh_TW |
| dc.subject.keyword | amyotrophic lateral sclerosis (ALS),C9ORF72,hexanucleotide repeat expansion,dipeptide repeats,poly-glycine-arginine (poly-GR),poly-proline-arginine (poly-PR),helix,membrane penetration,sulfated disaccharide, | en |
| dc.relation.page | 173 | - |
| dc.identifier.doi | 10.6342/NTU202400689 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2024-02-18 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 跨領域神經科學國際研究生博士學位學程 | - |
| dc.date.embargo-lift | 2029-02-15 | - |
| 顯示於系所單位： | 跨領域神經科學國際研究生博士學位學程 | |
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