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研究生:張景曜
研究生(外文):Ching-Yao Chang
論文名稱:脫附型電噴灑游離法質譜成像探討多系統萎縮症患者腦區的脂質混亂及其與 α- 突觸核蛋白聚集的空間關聯研究
論文名稱(外文):Exploring Lipid Disturbances and its Spatial Association with α-Synuclein Aggregation in MSA Patient Brain Regions via Desorption Electrospray Ionization Mass Spectrometry Imaging
指導教授:曾宇鳳
指導教授(外文):Yufeng Jane Tseng
口試委員:蕭明熙陳文進郭明哲
口試委員(外文):Ming-Shi ShiaoWen-Chin ChenMing-Che Kuo
口試日期:2023-10-27
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生醫電子與資訊學研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2023
畢業學年度:112
論文頁數:77
中文關鍵詞:脫附型電噴灑游離法質譜成像脂質混亂分子分佈α-突觸核蛋白多系統萎縮症
外文關鍵詞:Desorption electrospray ionization mass spectrometry imaging (DESI- MSI)lipid disturbancesmolecular distributionα-synucleinmultiple system atrophy
DOI:10.6342/NTU202304442
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多系統萎縮症是一種罕見的神經退化疾病,因伴隨著α-突觸核蛋白的異常堆積而被歸類為一種共核蛋白病。過去有許多研究觀察到多系統萎縮症病人血漿及腦脊髓液中的代謝體變化,但因α-突觸核蛋白堆積導致的代謝體分佈異常仍不清楚。
脫附型電噴灑游離法質譜成像利用軟性離子化技術,幫助辨識並呈現出組織上的分子分佈。我們將脫附型電噴灑游離法質譜成像應用在12個受到多系統萎縮症影響的腦區,包含了前額葉皮質、眶額葉皮質、運動皮質、感覺皮質、枕葉皮質、胼胝體、鉤束、視丘、殼核、尾狀核、小腦蚓部、大腦小腦(小腦外側),比較疾 病與正常組織的脂質表現及其空間分佈。另外,我們利用免疫組織染色法得到α-突觸核蛋白堆積之分佈,將質譜影像及組織染色影像進行空間對準來觀察蛋白質堆積及脂質分佈的空間關聯性。
本研究證實了脫附型電噴灑游離法質譜成像應用於多系統萎縮症相關脂質混亂的可應用性,簡化樣本製備程序並且減少游離法對於組織的傷害。我們也發現多系統萎縮症對於不同腦區造成的脂質混亂以及α-突觸核蛋白與這些脂質分子分佈的空間關聯。
Multiple system atrophy (MSA) is a rare neurodegenerative disease categorized as a synucleinopathy characterized by the abnormal accumulation of α-synuclein. Metabolite changes have been observed in MSA patients' biofluids, such as plasma and cerebrospinal fluid. However, understanding the spatial distribution of these metabolites in different brain regions is still limited.
Desorption electrospray ionization mass spectrometry imaging (DESI-MSI) is a soft ionization technique that can identify and visualize the distribution of molecules in tissues. Here, we applied DESI-MSI to 12 different regions of human brain tissues, including the prefrontal cortex, orbitofrontal cortex, motor cortex, sensory cortex, occipital cortex, corpus callosum, uncinate fascicle, thalamus, putamen, caudate, vermis, and cerebrocerebellum, thus covering most of the affected brain regions in MSA patients. We compared the lipid expression of fresh frozen samples and investigated the distribution of the altered lipids. Additionally, we used immunohistochemistry (IHC) staining to visualize the spatial distribution of α-synuclein. We performed image registration of histological images and mass spectrometry images to explore the correlation between the distribution of α-synuclein and the identified lipids.
Our findings demonstrated the utility of DESI-MSI in analyzing MSA-related lipid disturbances in brain tissues with a simple sample preparation process and minimal tissue damage. Moreover, our study provides insight into the spatial distribution of lipids in different brain regions affected by MSA and their correlation with the distribution of α- synuclein.
口試委員會審定書 #
誌謝 i
中文摘要 ii
ABSTRACT iii
CONTENTS v
LIST OF FIGURES viii
LIST OF TABLES x
GLOSSARY xi
Chapter 1 Introduction 1
1.1  Mass Spectrometry Imaging (MSI) 1
1.2  Medical Applications of MSI 2
1.3  Multiple System Atrophy (MSA) 5
1.4  Known Metabolite Alterations in MSA patients in Previous Works 7
1.4.1  Lipids 7
1.4.2  Neurotransmitters 9
1.4.3  Other Metabolites 10
1.5 Aims 11
Chapter 2 Materials and Methods 12
2.1 Sample Preparation 12
2.2  DESI-MSI and Histological Staining 12
2.3  Image Registration 13
2.4  Peak Annotation and Statistical Analysis 14
2.5  Pathway Analysis 16
2.6  Dimensionality Reduction and Clustering Analysis 17
Chapter 3 Results 19
3.1  Metabolite Annotation and Statistical Analysis 19
3.2  Related Pathways and Regional Differences 22
3.3  Clustering Analysis and The Correlation with α-Synuclein Distribution 28
3.3.1  Clustering 28
3.3.2  The Distribution of α-Synuclein Accumulation across the 12 Brain Regions 31
3.3.3  The Spatial Correlation of α-Synuclein Accumulation and Lipid Distribution 34
Chapter 4 Discussion 47
4.1 Major Observations 47
4.1.1 DESI-MSI can be used to quickly construct and assess spatial molecular changes in tissue 47
4.1.2 Pathway Analysis Revealed Different Patterns of Lipid Changes among Brain Regions 48
4.1.3 The IHC staining Confirmed the Presence of α-Synuclein Accumulation in Different Brain Regions 54
4.1.4 Lipid Alterations Are Hypothesized to Be Related to General Clinical Presentations of MSA in Some Brain Regions 55
4.1.5 The Distribution of α-Synuclein is Spatially Correlated with the Lipid Pattern Detected by MSI 63
4.2 Limitations 64
Chapter 5 Conclusions 67
REFERENCE 68
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