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研究生:陶治傑
研究生(外文):TAO, CHIH-CHIEH
論文名稱:表觀遺傳調控第一型組蛋白去乙醯酶的類小泛素化修飾可作為對抗乙型類澱粉蛋白毒性的內生性防禦機制-以阿茲海默氏症小鼠為動物模式
論文名稱(外文):Epigenetic Regulation of HDAC1 SUMOylation As an Endogenous Defense Against Aβ Toxicity in a Mouse Model of Alzheimer’s Disease
指導教授:李小媛李小媛引用關係
指導教授(外文):LEE, HSIAO-YUAN
口試委員:李小媛廖永豐陳韻如陳景宗李怡萱
口試委員(外文):LEE, HSIAO-YUANLIAO, YUNG-FENGCHEN, YUN-RUCHEN, JIN-CHUNGLEE, YI-HSUAN
口試日期:2017-03-17
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
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:2017
畢業學年度:105
語文別:中文
論文頁數:128
中文關鍵詞:第一型組蛋白去乙醯酶類小泛素化修飾神經保護阿茲海默氏症
外文關鍵詞:HDAC1SUMOylationCREBMcl-1 gene expressionneuroprotectionAlzheimer’s disease
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阿茲海默氏症 (Alzheimer's disease) 為一種慢性神經退化性疾病,其最主要於病理診斷上的特徵為大量堆積於腦部組織內的老化斑塊 (senile plaque),此斑塊主要的成分為乙型類澱粉蛋白 (amyloid beta,Aβ),目前已知乙型類澱粉蛋白於腦部會產生神經毒性並且導致神經細胞死亡。然而在面臨Aβ刺激損傷下的內生性保護機制仍然不是十分了解。在此我們發現於大白鼠海馬迴中給予急性Aβ刺激下,透過活化MAPK/ERK路徑,會增加protein inhibitor of activated STAT 1 (PIAS1) 與myeloid cell leukemia-1 (Mcl-1) 的表現量,並且PIAS1表現量的增加強化了第一型組蛋白去乙醯酶 (HDAC1) 於其第444位置之離胺酸 (Lys-444) 與第476位置之離胺酸 (Lys-476) 的類小泛素化修飾 (SUMOylation)。透過siRNA事先抑制PIAS1的表現,則會降低內生性HDAC1類小泛素化修飾的程度並阻斷Aβ對Mcl-1表現量增加的效果。在大白鼠腦中,給予brain-derived neurotrophic factor (BDNF)、insulin-like growth factor-1 (IGF-1) 和corticotropin-releasing factor (CRF) 處理,均可引起HDAC1 類小泛素化修飾的增加。HDAC1被類小泛素化修飾後會減弱其與cAMP response element binding protein (CREB) 的結合能力,進而增強CREB與Mcl-1 promoter的結合,因此致使Aβ刺激誘導Mcl-1的表現。利用慢病毒轉導可表現類小泛素化修飾的HDAC1之載體(SUMO-modified lenti-HDAC1 vector) 到APP/PS1小鼠的海馬迴區域中,可成功挽救其在空間學習記憶 (spatial learning and memory)、情境恐懼制約 (contextual fear memory) 與長期增益效果 (long-term potentiation,LTP) 的認知缺陷,並且在APP/PS1的小鼠海馬迴中,減少類澱粉蛋白斑塊 (amyloid plaque) 的堆積與降低CA1區域的凋亡細胞數量。同時, HDAC1的類小泛素化修飾會減弱其與腦啡肽酶之啟動子 (neprilysin promoter) 的結合程度。綜合以上的結果顯示,作為抵抗Aβ毒性的自然防禦機制,HDAC1 類小泛素化修飾扮演著十分重要的角色,並且在對抗阿茲海默氏症上提供另一種治療的策略。
Amyloid-β (Aβ) produces neurotoxicity in the brain and causes neuronal death, but the endogenous defense mechanism that is activated on Aβ insult is less well known. Here we found that acute Aβ increases the expression of PIAS1 and Mcl-1 via activation of MAPK/ERK, and Aβ induction of PIAS1 enhances HDAC1 SUMOylation at Lys-444 and Lys-476 in rat hippocampus. Knockdown of PIAS1 decreases endogenous HDAC1 SUMOylation and blocks Aβ induction of Mcl-1. HDAC1 SUMOylation is induced by BDNF, IGF-1 and CRF in the rat brain. Sumoylated HDAC1 reduces it association with CREB, increases CREB binding to the Mcl-1 promoter and mediates Aβ induction of Mcl-1 expression. Transduction of SUMO-modified lenti-HDAC1 vector to the hippocampus of APP/PS1 mice rescues spatial learning and memory deficit, contextual fear memory and long-term potentiation impairment in APP/PS1 mice. It also reduces the amount of amyloid plaque and the number of apoptotic cells in CA1 area of APP/PS1 mice. Meanwhile, HDAC1 SUMOylation decreases HDAC1 binding to the neprilysin promoter. These results together reveal an important role of HDAC1 SUMOylation as a naturally occurring defense mechanism protecting against Aβ toxicity and provide an alternative therapeutic strategy against AD.
正文目錄............................I
表目錄.............................V
圖目錄.............................VI
英文縮寫............................XII
中文摘要............................XVI
英文摘要............................XVIII
緒論..............................1
第一節、學 習、記憶與海馬迴 (Learning, memory and hippocampus).1
第二節、阿茲海默氏症 (Alzheimer's disease)............3
第三節、類澱粉前驅蛋白 (Amyloid precursor protein,APP)..... 5
第四節、乙型類澱粉蛋白 (Amyloid beta,Aβ)............7
第五節、組蛋白去乙醯酶 (Histone deacetylase,HDAC)........12
第六節、第一型組蛋白去乙醯酶 (Histone deacetylase 1,HDAC1). ..15
第七節、類小泛素化修飾 (SUMOylation)...............16
第八節、Protein inhibitor of activated STAT1 (PIAS1) ......17
第九節、抗凋亡蛋白Mcl-1 (Myeloid cell leukemia-1,Mcl-1) ....18
實驗目的.............................21
材料與方法............................22
一、動物實驗與飼養 (Animals) ............ ......22
二、海馬迴組織與細胞株蛋白質均質液的製備 (Hippocampal lysate and cell lysate preparation) ................................23
三、免疫沉澱法與西方墨點法 (Immunoprecipitation (IP) and western blot) ...23
四、質體建構、細胞培養與DNA轉染 (Plasmid construction, cell culture and DNA transfection) ...............................26
五、慢病毒載體建構與使用製備 (Lentiviral vector construction and preparation) ...................................... 28
六、針對重組HDAC1蛋白的體外類小泛素修飾試驗 (In vitro SUMOylation assay for recombinant HDAC1 protein) .........................30
七、腦組織的HDAC1類小泛素化修飾試驗 (HDAC1 SUMOylation in the brain) ...................................... 31
八、HEK293T細胞株的HDAC1類小泛素化修飾試驗 (HDAC1 SUMOylation in HEK293T cells) ...................................... 32
九、針對CREB之DNA結合活性的生物素化寡核苷酸沉澱試驗(Biotinylated oligonucleotides pull-down assay for CREB DNA-binding activity) ...................................... 33
十、染色質沉澱試驗 (Chromatin immunoprecipitation (ChIP) assay) ...................................... 34
十一、細胞外區域電位紀錄 (Extracellular field potentiation recording) ...................................... 35
十二、所使用藥品 (Drugs) ..........................36
十三、海馬迴內藥物注射、質體DNA轉染與siRNA注射 (Intra-hippocampal drug infusion, plasmid DNA transfection and siRNA injection) ...................................... 36
十四、水迷宮學習實驗 (Water maze learning) .................38
十五、環境恐懼制約學習 (Contextual fear conditioning learning) .......39
十六、免疫螢光染色 (Immunofluorescence staining) ..............40
十七、凋亡蛋白3活性試驗 (Caspase 3 activity assay) .............42
十八、末端脫氧核苷酸轉移酶脫氧尿苷三磷酸切口末端標記試驗(Terminal deoxynucleotidyl transferase dUTP nick end labeling assay,TUNEL assay)... 42
十九、統計分析................................43
結果.....................................45
一、Aβ急性刺激下經由MAPK/ERK的活化,增加了PIAS1蛋白的表現,同時PIAS1蛋白調控Aβ所引起的Mcl-1蛋白表現............................ 45
二、大鼠海馬迴在急性Aβ刺激下,透過PIAS1蛋白增加了HDAC1的類小泛素化修飾......................................49
三、在細胞株與海馬迴中辨識出HDAC1被SUMO修飾的候選胺基酸位置..................................... 52
四、BDNF、IGF-1與CRF增加大鼠海馬迴HDAC1的類小泛素化修飾..................................... 55
五、HDAC1 類小泛素化修飾降低其與CREB的結合能力並增加CREB與Mcl-1啟動子的結合,進而調控了Aβ引起的Mcl-1表現.......................... 56
六、HDAC1類小泛素化修飾挽救APP/PS1小鼠的突觸與記憶缺失..................................... 61
七、HDAC1 SUMOylation減少APP/PS1小鼠的類澱粉斑塊與凋亡細胞..................................... 63
討論...........................67
結論...........................76
參考文獻.........................77
表............................90
圖............................91

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