請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20538
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林君榮 | |
dc.contributor.author | Kuo-Chen Wu | en |
dc.contributor.author | 吳國禎 | zh_TW |
dc.date.accessioned | 2021-06-08T02:52:20Z | - |
dc.date.copyright | 2017-09-13 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-08-14 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20538 | - |
dc.description.abstract | 巴金森氏症(Parkinson′s disease)是一種與老化相關的神經退化性疾病,大腦黑質體的多巴胺神經元減少以及神經元內形成α-突觸核蛋白(α-synuclein)蛋白聚集體(Lewy bodies)為其主要病理特徵,目前廣泛認為環境或內生性神經毒素以及基因變異等多項危險因子可能是致病原因,然而詳細的病理機轉仍然不明。細胞膜轉運蛋白(membrane transporters)對於體內潛在神經毒性物質的分布與平衡扮演重要的角色,因此,本研究論文主要目的為探討細胞膜轉運蛋白與巴金森氏症病理機轉之間的關係。在第一部分的研究,我們發現老化及發炎以這兩個巴金森氏症重要的危險因子會調控有機陽離子轉運蛋白(organic cation transporters)包含Oct1、Oct2及Pmat於血腦屏障(blood-brain barrier)上的表現,進而影響有機陽離子神經毒性物質在腦內的濃度與其神經毒性。在第二部分的研究,我們發現人類大腦微膠細胞(microglia)內有表現自然抗性相關巨噬細胞蛋白-1(natural resistance-associated macrophage protein-1; Nramp1)蛋白,過去研究認為該蛋白能藉由調控溶酶體鐵質平衡來防禦外來病菌感染,而我們首次發現在高鐵質的病理狀態下,過度表現Nramp1蛋白能幫助微膠細胞降解細胞外α-synuclein oligomers;另外,我們發現人類多巴胺神經元內也有表現Nramp1蛋白,而在巴金森氏症病患的多巴胺神經元內該蛋白表現量低下,我們進一步的研究證實Nramp1蛋白表現可以正向調控細胞內α-synuclein的降解,並對於MPTP/MPP⁺誘發的巴金森氏症實驗模型有神經保護的作用。綜合以上結果,本研究論文以細胞膜轉運蛋白的角度探討神經毒性物質及鐵質平衡異常於巴金森氏症病理機轉之角色,並建立體內自然防禦機制與神經退化性疾病的相關性。 | zh_TW |
dc.description.abstract | Parkinson′s disease (PD) is an age-related neurodegenerative disease, characterized by a progressive loss of dopaminergic neurons and the presence of intracellular proteinaceous inclusions containing aggregated α-synuclein (known as Lewy bodies). Multiple etiological causes, including genetic factors, environmental insults, and endogenous neurotoxins, have been linked to the development of PD. However, the pathological mechanisms remain unclear. Membrane transporters play an important role for the distribution of their substrates including neurotoxic substances (either exogenous or endogenous origins). Therefore, the aim of this thesis is to gain insight into the involvement of membrane transporters in PD pathogenesis. In the first part, we show that normal aging and inflammation, two key risk factors for PD, can regulate the expression of organic cation transporters (including Oct1, Oct2, and Pmat) at the blood-brain barrier and subsequently affect brain distribution of toxic organic cations and their neurotoxicity. In the second part, we find that microglia express natural resistance-associated macrophage protein-1 (Nramp1) that is a lysosomal metal ion transporter responsible for natural resistance to infection with pathogens. We demonstrate that Nramp1 expression in microglia contributes to the degradation of extracellular α-synuclein oligomers under iron overload condition. Moreover, we show that Nramp1 is also expressed in dopaminergic neurons, of which the expression level is significantly reduced in PD patients. We further demonstrate that its expression has a protective role against MPTP/MPP⁺-induced up-regulation of α-synuclein and neurotoxicity. Taken together, the works described in this thesis support the pathological roles of neurotoxins and iron dyshomeostasis in PD by investigating membrane transporters and provide a connection between host defense mechanism and neurodegenerative diseases. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:52:20Z (GMT). No. of bitstreams: 1 ntu-106-D01423101-1.pdf: 7191234 bytes, checksum: 64f24389452f5d46a96d0bc9662078a3 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 中文摘要 i
Abstract ii Table of Contents iv List of Figures x List of Tables xvi Abbreviations xvii 1 Introduction 1 2 Literature review 4 2.1 Brief historical review of PD 4 2.2 Epidemiology of PD 5 2.3 Pathological hallmarks of PD 6 2.4 Etiological factors 7 2.4.1 Genetic factors 7 2.4.2 Environmental insults 9 2.4.3 Endogenous neurotoxins 12 2.4.4 Interaction of multiple etiological factors 14 2.5 Roles of membrane transporters in PD 15 2.5.1 Dopamine transporter (DAT) 16 2.5.2 Organic cation transporters (OCTs) 16 2.5.3 SLC11 metal ion transporters 18 2.6 Summary 19 3 Expression and regulation of organic cation transporters (including Oct1, Oct2, and Pmat) at the blood-brain barrier and the implication to the transport of neurotoxins 24 3.1 Abstract 24 3.2 Introduction 26 3.3 Results 30 3.3.1 The expression of Pmat in BMVs and brain parenchyma 30 3.3.2 Cellular localization of PMAT/Pmat in BMECs 30 3.3.3 The effect of LPS on Pmat expression in brain regions and in BMVs of C57BL/6 mice 31 3.3.4 The effect of LPS treatment on brain concentrations of 1-benzyl-TIQ 32 3.3.5 Effect of aging on the expression of Oct1, Oct2, and Pmat in the brain and BMVs of C57BL/6 mice 33 3.3.6 Brain extracellular levels of MPTP and MPP⁺ in C57BL/6 mice, Swiss mice, Oct1/2-/- mice, and wild-type FVB mice 34 3.3.7 Plasma levels of MPTP and MPP⁺ in C57BL/6 mice, Oct1/2-/- mice, and WT FVB mice 36 3.3.8 Dopaminergic toxicity of MPTP in senescent mice and Oct1/2-/- mice 36 3.4 Discussion 38 3.5 Brief summary 45 3.6 Limitations and challenges 46 3.7 Materials and methods 47 4 The critical role of Nramp1 in degrading α-synuclein oligomers in microglia under iron overload condition 73 4.1 Abstract 73 4.2 Introduction 74 4.3 Results 77 4.3.1 α-Synuclein oligomers are identified in microglia in the striatum of PD patients, but not in non-PD controls 77 4.3.2 Iron is accumulated in microglia in the striatum of PD patients 78 4.3.3 The accumulation of α-synuclein oligomers and iron in microglia in the substantia nigra of PD patients 79 4.3.4 Nramp1 is expressed in microglia and neurons in the striatum of human brain 80 4.3.5 The function of Nramp1 affects the degradation of oligomeric α-synuclein and cathepsin D activity in RAW264.7 cells under iron exposure 81 4.3.6 The function of Nramp1 affects the degradation of oligomeric α-synuclein and cathepsin D activity in BV-2 microglia cells under iron exposure 83 4.3.7 Mice carrying functional Nramp1 can restore the inhibitory effect of iron on the degradation of infused oligomeric α-synuclein 86 4.3.8 The role of microglia in degrading oligomeric α-synuclein in mice of different Nramp1 function under iron overload condition 87 4.4 Discussion 88 4.5 Brief summary 92 4.6 Limitations and challenges 92 4.7 Materials and methods 93 5 Expression of Nramp1 protects mice and neuroblastoma cells from MPTP/MPP+-induced up-regulation of α-synuclein and neurotoxicity 131 5.1 Abstract 131 5.2 Introduction 132 5.3 Results 135 5.3.1 Iron deposit and α-synuclein accumulation in chronic MPTP-intoxicated mice with functional and nonfunctional Nramp1 135 5.3.2 Dopaminergic neurotoxicity in chronic MPTP-intoxicated mice with functional and nonfunctional Nramp1 136 5.3.3 Pathological features and Nramp1 expression in the substantia nigra of PD patients 137 5.3.4 Low-dose MPP⁺ treatment increased protein, but not mRNA, expression and the aggregation of α-synuclein in neuroblastoma cells 138 5.3.5 Low-dose MPP⁺ up-regulated DMT1+IRE expression but down-regulated Nramp1 expression in neuroblastoma cells 140 5.3.6 Overexpression of Nramp1 inhibited low-dose MPP⁺-induced up-regulation of α-synuclein and attenuated low-dose MPP⁺-induced neurotoxicity in neuroblastoma cells 141 5.4 Discussion 142 5.5 Brief summary 148 5.6 Limitations and challenges 148 5.7 Materials and methods 149 6 Conclusion 175 6.1 General discussion 175 6.2 Future directions 178 References 181 | |
dc.language.iso | en | |
dc.title | 細胞膜轉運蛋白在巴金森氏症致病機轉上扮演的角色探討
第一部分:老化及發炎對腦部微血管上有機陽離子轉運蛋白表現與神經毒素運送的影響 第二部分:Nramp1對α-synuclein降解及MPTP/MPP⁺引發神經毒性的影響 | zh_TW |
dc.title | Roles of membrane transporters in the pathogenesis of Parkinson′s disease
Part I: Effects of aging and inflammation on the expression of organic cation transporters and the mediated transport of neurotoxins in brain microvessels Part II: Nramp1 contributes to the degradation of α-synuclein and its implication to MPTP/MPP⁺-induced neurotoxicity | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 尹相姝,陳瓊美,陳儀莊,伍安怡,孔繁璐 | |
dc.subject.keyword | 巴金森氏症,神經毒素,α-突觸核蛋白,有機陽離子轉運蛋白,自然抗性相關巨噬細胞蛋白-1, | zh_TW |
dc.subject.keyword | Parkinson′s disease,neurotoxins,α-synuclein,organic cation transporters,natural resistance-associated macrophage protein-1, | en |
dc.relation.page | 199 | |
dc.identifier.doi | 10.6342/NTU201703082 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2017-08-14 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-106-1.pdf 目前未授權公開取用 | 7.02 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。