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研究生:黎少婷
研究生(外文):Sau-TingLai
論文名稱:探討亨廷頓相關蛋白40對於細胞聚集體形成及基因轉殖小鼠生化特性之影響
論文名稱(外文):Role of Endogenous HAP40 in Cellular Aggregate Formation and Biochemical Characterization of Transgenic HAP40 Mouse
指導教授:何盧勳
指導教授(外文):Lu-Shiun Her
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:80
外文關鍵詞:HuntingtinHuntington’s diseaseHuntingtin-associated protein 40AggregatesUbiquitin-proteasome systemAutophagy
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Huntington’s disease (HD) is a prevalent neurodegenerative disorder caused by the expansion of polyglutamine tract in the huntingtin (Htt) protein. It is primarily characterized by progressive loss of brain and motor functions, and the accumulation of aggregates constituted by mutant Htt. Huntingtin associated protein 40 (HAP40) is discovered to interact and form a complex with Htt which regulates early endosomes. To date, however, the function of HAP40 remains poorly understood. This study attempted to investigate the role of HAP40 in cell culture and transgenic mouse models by the knockdown and overexpression approaches. The results revealed that knockdown of endogenous HAP40 was able to increase cellular aggregates formation. In conjunction with recent findings in the lab revealing an increase in cellular aggregates formation due to upregulation of HAP40, this study had shown that both downregulation and upregulation of HAP40 resulted in accumulation of aggregates in cells. Downregulation of HAP40 resulted in a significant increment in the immunofluorescence intensity of UbG76V-GFP/mCherry and a decrease in ubiquitin-proteasome system (UPS)-associated proteins: PSMD4 and UCHL1 in the cells. Likewise, overexpression of HAP40 had increased the UbG76V-GFP/mCherry immunofluorescence intensity and decreased ADRM1 level. Conversely, knockdown and overexpression of HAP40 did not activate autophagic activity. These results further imply that the induction of aggregates accumulation by HAP40 may be due to UPS impairment. In the transgenic mouse model, overexpression of HAP40 did not seem to affect the clasping phenotype of the FU-mCherry mHAP40 mice. The biochemical analysis of the cortex and striatum mice brain lysates demonstrated no significant changes in the UPS-associated proteins across genotype or brain region differences. However, the UPS function in the mice brains remain inconclusive as a more in depth experimental approach is required to further confirm this. This study has provided an insight of the role of HAP40 in cellular aggregates formation and UPS activity.
ABSTRACT I
ACKNOWLEDGMENTS III
TABLE OF CONTENTS IV
LIST OF TABLES VII
LIST OF FIGURES VIII
ABBREVIATIONS IX
CHAPTER 1 INTRODUCTION 1
1.1 Polyglutamine (PolyQ) Diseases 1
1.2 Huntington’s Disease (HD) 2
1.3 Huntingtin (Htt) 2
1.4 Huntingtin Associated Protein 40 (HAP40) 4
1.5 Htt Aggregation in HD 5
1.6 Ubiquitin-Proteasome System (UPS) 5
1.7 Autophagy 6
OBJECTIVES OF STUDY 8
CHAPTER 2 MATERIALS AND METHODS 9
2.1 Antibodies and Plasmids 9
2.1.1 Antibodies 9
2.1.2 Plasmids 10
2.2 Animals 10
2.2.1 DNA Extraction from Tail Biopsy 11
2.2.2 Polymerase Chain Reaction (PCR)-based Genotyping 11
2.2.3 Clasping Test 12
2.2.4 Mouse Brain Tissue Collection 12
2.3 Cell Cultures 13
2.3.1 Cell Lines 13
2.3.2 Thawing Cryopreserved Cell Lines 13
2.3.3 Subculture of Cell Lines 14
2.3.4 Cell Count 14
2.3.5 Cryopreservation of Cell Lines 14
2.4 Transfection 15
2.5 Tubastatin A Treatment 16
2.6 Immunofluorescence Staining 16
2.7 Protein Extraction 16
2.7.1 Mouse Brain Tissues Protein Extraction 16
2.7.2 Cells Protein Extraction 17
2.7.3 Protein Assay 17
2.8 Western Blot 18
2.8.1 Gel Electrophoresis and Electrotransfer 18
2.8.2 Blocking and Antibody Incubation 18
2.8.3 Imaging and Data Analysis 18
2.9 Statistical Analysis 19
CHAPTER 3 RESULTS 20
3.1 Effects of HAP40 on QP72-GFP-induced aggregates formation 20
3.2 Effects of HAP40 overexpression and knockdown on UPS 21
3.3 Effects of HAP40 overexpression and knockdown on UPS-associated proteins 22
3.4 Effects of HAP40 on UPS-associated proteins in N2a cells consisting QP72-GFP-induced aggregation 24
3.5 Effects of HAP40 on autophagy 24
3.6 Effects of HAP40 on mitochondria-associated proteins 25
3.7 Effects of Tubastatin A on aggregates formation without HAP40 overexpression in N2a cells 26
3.8 HAP40 expression level in FU-mCherry mHAP40 transgenic mice 27
3.9 Clasping behavior of FU-mCherry mHAP40 transgenic mice 28
3.10 Biochemical analysis of FU-mCherry mHAP40 transgenic mice on UPS-associated proteins 28
3.11 Biochemical analysis of FU-mCherry mHAP40 transgenic mice on mitochondria-associated proteins 29
CHAPTER 4 DISCUSSION 30
REFERENCES 35
FIGURES AND FIGURE LEGENDS 42

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