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研究生:吳春嫺
研究生(外文):Chun-Hsien Wu
論文名稱:台灣族群帕金森氏症Parkin及HTRA2基因變異的分子遺傳及功能研究
指導教授:李桂楨李桂楨引用關係
指導教授(外文):Guey-Jen Lee-Chen
學位類別:碩士
校院名稱:國立臺灣師範大學
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
畢業學年度:97
語文別:中文
論文頁數:86
中文關鍵詞:ParkinHTRA2帕金森氏症
外文關鍵詞:ParkinHTRA2Parkinson's disease
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PARK2與PARK13分別與體染色體隱性遺傳及偶發性帕金森氏症(Parkinson's disease;簡稱PD)相關。PARK2基因產物Parkin具ubiquitin E3 ligase功能,而PARK13基因產物HTRA2則與細胞凋亡相關。本研究延續先前的PARK2 cDNA定序(管, 2007),分析台灣帕金森氏症患者Parkin的基因變異。結果共發現二個缺失突變(Ex2-3del、Ex5del)、一個點突變(R334C)、兩個多型性(S167N、V380L)及一個新穎的內含子9插入突變(c.1084intron+),此插入突變與內含子9上的-6g>a (IVS9 g>a)的多型性點相關。進一步對所蒐集的病人與性別、年齡相當的正常人進行S167N、V380L的病例-對照組分析,結果顯示V380L C等位基因頻率在病人族群中明顯較正常人族群低,且和低帕金森氏症感受性相關。Ex5del缺失突變與正常人淋巴細胞的分析結果顯示,病人淋巴細胞的Caspase-3活性顯著高於正常人,粒線體膜電位分析結果亦顯示病人淋巴細胞的細胞凋亡顯著高於正常人,在staurosporine或去血清處理下,病人淋巴細胞存活率顯著低於正常人。在HTRA2基因分析方面,HTRA2 cDNA定序結果發現二個新穎的點突變(R36W與T215M)。進一步建構EGFP標記的cDNA質體,表現於HEK-293T及SK-N-SH細胞,次細胞分層、西方轉漬、螢光顯微鏡分析結果顯示,R36W與T215M蛋白皆有成熟型蛋白生成且座落於粒線體,但R36W蛋白成熟型表現量較野生型低,T215M蛋白則表現異常分子量的前軀及成熟蛋白。
PARK2 and PARK13 are involved in autosomal recessive juvenile parkinsonism and sporadic Parkinson’s disease (PD), respectively. The PARK2 gene product Parkin has ubiquitin E3 ligase activity, whereas PARK13 gene product HTRA2 is located in the mitochondrial intermembrane space and released into the cytosol during apoptosis. In the present study PARK2 mutations were analyzed in a cohort of Taiwanese PD patients by using direct cDNA sequencing. Two deletions (Ex2-3del and Ex5del), one point mutation (R334C), one insertion (c.1084intron+) and two reported SNPs (S167N and V380L) in Parkin were identified. The c.1084intron+ was due to a novel g-a transition SNP at position -6 of a cryptic splice acceptor site within IVS9 (-6g>a). The association of Parkin polymorphisms S167N and V380L with PD were analyzed using a case-control study. Although the difference is not significant, the V380L C allele was notably lower in PD patients than the controls, and a trend toward decrease in risk of developing PD was evident. In lymphoblastoid cells, caspase-3 activity and loss of mitochondrial membrane potential in cells with Ex5del were significantly higher than that of the control cells. Treatment of staurosporine significantly increases cell death in the cells with e Ex5del. Screening of the HTRA2 cDNA revealed two novel point mutations (R36W and T215M). The EGFP-tagged HTRA2 constructs were prepared for transient expression in HEK-293T and SK-N-SH cells. Subcellular fractionation, Western blot and fluorescence microscopy examination revealed that both R36W and T215M mature proteins localized to mitochondria. However, the amount of R36W mature protein is less than that of wild type. Also unusual precursor and mature proteins were observed with T215M mutation.
目錄 I
中文摘要 VI
Abstract VII
圖表目錄 VIII
壹、緒論 1
一、帕金森氏症 1
(一)臨床病徵 1
(二)神經病理學 2
(三)致病原因 2
(四)致病途徑 3
二、帕金森氏症的遺傳分析 4
三、Parkin基因 5
(一) Parkin的構造與表現 6
(二) Parkin的功能 7
(三) Parkin基因變異與帕金森氏症 8
四、HTRA2基因 8
(一) HTRA2的構造與表現 9
(二) HTRA2的功能 10
(三) HTRA2基因變異與帕金森氏症 10
(四) HTRA2與其它神經退化性疾病 11
貳、研究目的 12
參、研究材料與方法 13
一、研究樣品 13
二、細胞培養 13
三、西方轉漬法(Western blot) 14
四、Parkin cDNA增幅及定序 15
五、Parkin基因S167N、V380L多型性與台灣族群PD感受性分析 15
(一)聚合酶連鎖反應(PCR) 16
(二)限制酶片段長度多型性分析(RFLP) 16
(三)統計分析 16
六、台灣族群Parkin基因R334C突變檢測 17
七、Parkin Ex5del缺失突變淋巴細胞株的粒線體功能分析 17
(一) Caspase-3活性分析 18
(二)粒線體膜電位分析 18
(三)淋巴細胞的存活率分析 19
八、HTRA2 cDNA增幅及定序 19
九、台灣PD族群HTRA2基因R36W及T215M突變檢測 20
(一)聚合酶連鎖反應(PCR) 20
(二)限制酶片段長度多型性分析(RFLP) 20
(三) R36W突變的家族分析 21
十、HTRA2基因R36W及T215M突變的功能分析 21
(一) pEGFP-N1-HTRA2重組質體的建構 21
(二)轉染(transfection) 22
(三)次細胞分層及西方轉漬分析 22
(四)螢光顯微鏡觀察 23
肆、結果 25
一、PD患者Parkin基因突變 25
(一) S167N G>A與V380L G>C多型性 25
(二) R334C C>T突變 26
(三) Ex2-3del、Ex5del缺失突變 26
(四) c.1084intron+插入突變 26
二、Parkin基因S167N、V380L多型性與台灣族群PD感受性 27
三、Parkin Ex5del缺失突變淋巴細胞株的粒線體功能分析 27
(一) Caspase-3活性分析 28
(二)粒線體膜電位分析 28
(三)淋巴細胞的存活率分析 29
四、PD患者HTRA2基因突變 30
(一) R36W C>T突變 30
(二) T215M C>T突變 30
(三) R36W突變的家族分析 31
五、HTRA2突變之功能分析 31
(一) EGFP標記的HTRA2 cDNA選殖 31
(二) EGFP標記的HTRA2 cDNA表現 32
(三) HTRA2-EGFP融合蛋白的螢光顯微鏡觀察 32
六、突變及多型性的序列比對 32
(一) S167N、V380L多型性及R334C突變的序列比對 33
(二) R36W及T215M突變的序列比對 33
伍、討論 34
一、Parkin基因突變 34
(一) Ex2-3del、Ex5del缺失突變 34
(二) R334C C>T突變 35
(三) c.1084intron+插入突變 36
(四) S167N、V380L多型性與台灣族群PD感受性 36
(五) Parkin Ex5del缺失突變淋巴細胞株的粒線體功能分析 37
二、HTRA2基因突變 40
(一) R36W C>T突變 40
(二) T215M C>T突變 41
(三) HTRA2基因R36W及T215M突變的功能分析 41
陸、參考文獻 43
柒、附錄圖表 54
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