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研究生:胡淑惠
研究生(外文):Hu Shu Hui
論文名稱:探討突變第三型運動失調質引起橋腦核神經元死亡的分子機轉
論文名稱(外文):Molecular mechanism underlying mutant ataxin-3-induced neuronal death of pontine nuclei
指導教授:王鴻利
指導教授(外文):H. L. Wang
學位類別:碩士
校院名稱:長庚大學
系所名稱:生物醫學研究所
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:2009
畢業學年度:97
論文頁數:77
中文關鍵詞:第三型脊髓小腦性運動失調症轉錄異常核因子kappaB
外文關鍵詞:Spinocerebellar ataxia type 3transcriptional abnormalityNF-kappaB
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第三型脊髓小腦性運動失調症(Spinocerebellar ataxia type 3; SCA3)或麥歇多喬瑟夫疾病是一種因第三型運動失調質(ataxin-3)基因上負責轉譯成麩酸胺(glutamine)的CAG核酸序列增長所引起的遺傳性體染色體顯性神經退化性疾病。正常ataxin-3於靠近碳基端處含有12-41個麩酸胺,而引起SCA3的突變之ataxin-3在碳基端的麩酸胺則延長至62-84個。Ataxin-3的功能目前認為其是一個泛素蛋白酶(ubiquitin protease)及轉錄作用抑制子(transcriptional repressor)。雖然ataxin-3廣泛表現於腦部,在SCA3中,突變多麩酸胺 ataxin-3只會引起橋腦核、黑質、小腦、紋狀體及脊髓的神經元退化。
在本實驗中,我們已成功建立了表現突變多麩酸胺 之ataxin-3 (ataxin-3-Q79)的基因轉殖鼠,以作為研究SCA3的動物模式。表現ataxin-3-Q79的基因轉殖鼠在四個月大時發病,並伴隨著運動功能障礙的問題,隨後的幾個月裡神經系統的症狀也逐漸惡化。免疫組織染色實驗指出,四個月大SCA3小鼠的橋腦核神經元死亡較小腦神經元死亡顯著,這表示我們的ataxin-3-Q79小鼠適合用於研究突變多麩酸胺 ataxin-3引發選擇性橋腦核神經元死亡的分子機制。
在多麩酸胺神經退化性疾病(polyglutamine neurodegenerative diseases) 中細胞核內表現突變多麩酸胺蛋白質為發病所必須,且突變蛋白表現在細胞核會促使基因轉錄異常而導致神經元功能異常及死亡。因此,我們藉由了解四個月大的SCA3小鼠橋腦核內基因表現的變化,來探討突變多麩酸胺 ataxin-3引發之轉錄異常是否會選擇性造成橋腦核神經元死亡。寡核苷酸微陣列技術(microarray)及即時定量反轉録-聚合酶鏈鎖反應(real-time RT-PCR)實驗結果顯示與控制組之非基因轉殖鼠比較,發現在四個月大的ataxin-3-Q79小鼠的橋腦核中,前列腺素D合成酶(Ptgds)的mRNA表現量下降以及核因子kappaB (NF-kappaB)抑制蛋白I kappa B alpha、糖皮質素誘發蛋白質(GILZ)、鋅手指蛋白Zac1、父系表現基因3 (Peg3)的mRNA表現量上升,然而在小腦及大腦皮質神經元Ptgds、I kappa B alpha、GILZ、Zac1與Peg3的mRNA表現量則無變化,因此,我們的研究結果顯示ataxin-3-Q79會引起區域特定性的轉錄失調而選擇性造成橋腦核神經元死亡。
轉錄因子NF-kappa B被認為會藉由誘導促存活蛋白質與抗細胞凋亡蛋白質表現以支持神經元存活,I kappa B alpha會與細胞質的NF-kappaB二聚體結合抑制NF-kappaB進入細胞核,而GILZ則會與組成NF-kappaB的次單元蛋白p65結合進而抑制NF-kappaB的活性。西方點墨法(Western blotting)結果顯示在四個月大的SCA3小鼠的橋腦核神經元中,表現在細胞質的NF-kappaB p65蛋白質量增加,而轉移入細胞核的p65蛋白量減少,更進一步利用電泳遷移率變動分析(EMSA)及RT-RCR證明在四個月大SCA3小鼠橋腦核內的NF-kappaB活性下降,而其正向調控的基因包含Bcl-xL、細胞凋亡抑制蛋白質2(IAP2)、X染色體連鎖細胞凋亡抑制蛋白質(XIAP)與錳超氧化物歧化酶(MnSOD)的mRNA表現量皆有減少的情形。因此,在橋腦核內,ataxin-3-Q79會促使I kappa B alpha和GILZ的mRNA表現量上升,進而抑制NF-kappaB正向調控的抗細胞凋亡分子的產生,可能是導致選擇性橋腦核神經元死亡的原因。
抑制組蛋白去乙醯化酶(HDAC)活性被認為會促進組蛋白廣泛的過度乙醯化(hyperacetylation),並逆轉基因轉錄異常的情形。SCA3小鼠接受HDAC抑制劑丁酸鈉(sodium butyrate)注射後,在四個月大時,運動功能有明顯改善,並橋腦核神經元死亡的數目有減少。給予每日注射sodium butyrate也扭轉ataxin-3-Q79所引發之橋腦核神經元內Ptgds和NF-kappaB正向調控基因的mRNA表現量下降及I kappa B alpha、GILZ、Peg3和Zac1 mRNA表現量上升的情形。
總結來說,本實驗的研究結果顯示ataxin-3-Q79會引起基因轉錄異常,進而抑制抗細胞凋亡的NF-kappaB之活性,而導致SCA3小鼠中橋腦核神經元選擇性死亡。此外,HDAC抑制劑sodium butyrate可逆轉ataxin-3-Q79引起的橋腦核內基因轉錄失調,並改善神經運動功能上的異常,因此,HDAC抑制劑也許可作為治療SCA3的藥物。
Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease is an inherited autosomal dominant neurodegenerative disorder caused by abnormal expansion of CAG repeats coding for polyglutamine tract within a protein called ataxin-3. Normal ataxin-3 contains 12- 41 glutamines near the C-terminus, and the polyglutamine tract expands to 62-84 glutamines in disease-causing mutant ataxin-3. Wild-type ataxin-3 is believed to function as an ubiquitin protease and a transcriptional repressor. In contrast to wide distribution of ataxin-3 in the brain, SCA3 neurodegeneration is mainly found in the pontine nuclei, substantia nigra, cerebellum, striatum, and spinal cord.
In the present study, we prepared SCA3 animal model by generating transgenic mice expressing polyglutamine-expanded ataxin-3-Q79. Ataxin-3-Q79 transgenic mice displayed motor dysfunction with an onset age of 4 months, and neurological symptoms deteriorated in the following months. Immunohistochemical staining indicated that the neuronal death in the pontine nuclei is more prominent than that observed in the cerebellum of 4-month-old SCA3 mice, suggesting our ataxin-3-Q79 mice were suitable model to study molecular mechanism of polyglutamine-expanded ataxin-3-induced selective neuronal death in the pontine nuclei.
Nuclear expression of polyglutamine-expanded proteins is required for the pathogenesis of polyglutamine neurodegenerative diseases and leads to neuronal dysfunction and cell death by causing transcriptional dysregulation. Therefore, we tested the involvement of transcriptional abnormality in causing selective neuronal death of pontine nuclei by identifying altered gene expressions in the pontine nuclei of 4-month-old ataxin-3-Q79 mice. Our microarray analysis and real-time RT-PCR indicated that compared to control non-transgenic mice, downregulated expression of Prostaglandin D synthetase (Ptgds) and upregulated expression of Zac1, Paternally expressed 3 (Peg3), glucocorticoid-induced leucine zipper (GILZ) and I kappa B alpha were observed in the pontine nuclei of 4-month-old ataxin-3-Q79 transgenic mice. Altered mRNA expressions of I kappa B alpha, GILZ, Peg3, Zac1 and ptgds were not observed in the cerebellum and neocortex. Our results provide the evidence that ataxin-3-Q79-induced region-specific transcriptional dysregulation causes selective and prominent neuronal death in the pontine nuclei.
Transcription factor nuclear factor-kappaB (NF-kappaB) is believed to support neuronal survival by inducing the expression of pro-survival and anti-apoptotic proteins. I kappa B alpha interacts with cytosolic NF-kappaB dimer and prevents nuclear translocation of NF-kappaB. GILZ binds to p65 subunit of NF-kappaB and inhibits NF-kappaB activity. Western blotting data showed that an increased cytoplasmic sequestration of NF-kappaB p65 and a reduced nuclear translocation of p65 subunit of NF-kappaB in the pontine nucliei of SCA3 transgenic mice. EMSA assay and real-time RT-PCR assay demonstrated the NF-kappaB activity and expression of NF-kappaB target genes, including Bcl-xL, manganese superoxide dismutase (MnSOD), inhibitor of apoptosis protein 2 (IAP2) and X-chromosome-linked IAP (XIAP) were decreased in the pontine nuclei of ataxin-3-Q79 transgenic mice. Thus, mutant ataxin-3-Q-79-induced upregulated expression of I kappa B alpha and GILZ is likely to cause neuronal death of pontine nuclei by inhibiting NF-kappaB-mediated transcription of anti-apoptotic factors.
The inhibition of histone deacetylase (HDAC) activity is expected to induce general hyperacetylation of histones and reverse transcription dysregulation. The HDAC inhibitor sodium butyrate treatment significantly improved motor performance and alleviated pontine neuronal death of 4-month-old ataxin-3-Q79 transgenic mice. Daily administration of sodium butyrate also reversed downregulated expression of Ptgds and NF-kappaB target genes and upregulated expression of I kappa B alpha, GILZ, Peg3 and Zac1 in the pontine nuclei of ataxin-3-Q79 mice.
In summary, the present study provides the evidence that ataxin-3-Q79-induced transcriptional abnormality, which impairs the activity of anti-apoptotic NF-kappaB, causes selective neuronal death in the pontine nuclei of SCA3 transgenic mice. HDAC inhibitor sodium butyrate reverses ataxin-3-Q79-induced transcriptional dysregulation in the pontine nuclei and ameliorates neurological phenotypes of ataxin-3-Q79 transgenic mice. Therefore, HDAC inhibitor might be a promising therapeutic agent for SCA3.
Abstract (Chinese) v
Abstract (English) viii
Abbreviations xi
Contents xii
I.Introduction 1
II. Specific aims 7
III. Materials and methods 8
3.1 Generation of transgenic mice 8
3.2 Southern blotting and PCR of tail DNA 8
3.3 Behavioral tests 9
3.4 Microarr ayanalysis 9
3.5 Real-time quantitative RT-PCR assay 10
3.6 Immunocytochemical staining 12
3.7 Nuclear and cytosolic extracts 12
3.8 Electrophoretic mobility shift assay (EMSA) of
NF-kappaB 13
3.9 Immunoblotting analysis of I kappa B alpha or
NF-kappaB p65 13
3.10 Sodium butyrate administration 14
3.11 Statistics 15
IV. Results 16
4.1 SCA3 transgenic mice displayed motor dysfunction and
neuron loss in the pontine nuclei with an onset age of
4 month 16
4.2 Microarray analysis of altered gene expressions in
the pontine nuclei of SCA3 transgenic mice 17
4.3 Confirmation of microarray data by real-time RT-PCR
and immunoblotting assays 19
4.4 The involvement of impaired NF-kappaB activity in
mutant ataxin-3-Q79 -induced neuronal death of pontine
nuclei 20
4.5 Impaired NF-B target gene expression in the pontine
nuclei of ataxin-3-Q79 transgenic mice 21
4.6 Sodium butyrate ameliorates pontine neuronal death,
improves motor performance and reverses transcriptional
dysregulation in the pontine nuclei of ataxin-3-Q79
transgenic mice. 22
V. Discussion 25
VI. References 31
VII. Table and figures 41
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