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研究生:江明璋
研究生(外文):Ming-Chang Chiang
論文名稱:藉由了解此失去調節的CREB,C/EBPa及14-3-3�窸J白質在漢丁頓氏舞蹈症之研究
論文名稱(外文):Transcriptional Dysregulation of Huntington’s disease - Functional roles of CREB, C/EBPa and 14-3-3��
指導教授:陳儀莊陳儀莊引用關係
指導教授(外文):Yijuang Chern
學位類別:博士
校院名稱:國立陽明大學
系所名稱:神經科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:英文
論文頁數:264
中文關鍵詞:漢丁頓舞蹈症A2A腺甘酸受體亞型尿素循環障礙紋狀體
外文關鍵詞:Huntington’s diseaseA2A adenosine receptorurea cycle deficiencyStriatal
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蛋白質不正常的堆積是造成神經退化疾病主要因素之一。漢丁頓舞蹈症是一種神經退化疾病,主要症狀是舞蹈症與精神病。致病原因是Huntingtin (Htt)基因第一表現子上出現重覆且延長的CAG核酸序列。所延長之CAG核酸序列轉譯成為重覆之麩胺醯酸,集結成Htt塊形,進一步造成病變。紋狀體神經細胞死亡,是漢丁頓氏舞蹈症發病的最早期的病理特徵。我們針對在紋狀體會大量表現的A2A腺甘酸受體亞型(A2A-R)功能是否會受到突變的漢丁頓蛋白質的影響 來研究。此篇論文主要在探討A2A-R啟動子是如何受到突變的漢丁頓蛋白(Huntingtin; Htt)之調控。首先突變的漢丁頓蛋白會抑制A2A-R的基因和啟動子表現在PC12和初級紋狀體神經細胞。若使用A2A-R的agonist (CGS21680,一個A2A-R刺激物)、forskolin和活化之CREB蛋白都可以提高被突變的漢丁頓蛋白所抑制A2A-R的啟動子表現,反之若用A2A-R的antagonist (CSC)、二個PKA抑制劑和突變的CREB蛋白則會破壞前者刺激物的作用。所以PKA和CREB蛋白是會參與調節A2A-R的啟動子表現。再來我們利用EMSA和突變的inactivation証實A2A-R的啟動子上有一個非典型的CRE site (TCCAGG),也發現了Htt突變蛋白藉由調控CREB蛋白來抑制A2A-R啟動子的機制。A2A-R的agonist (CGS21680)可以恢復受到Htt突變蛋白所影響的CREB蛋白和同時減少Htt突變蛋白的塊形。研究此A2A-R基因在Htt突變蛋白存在狀況下的基因調控及表現,可提供了未來探討Htt突變蛋白在調節其他轉錄因子上,極好的一個模型。我們的成果將促進對A2A腺甘酸受體亞型(A2A-R)的瞭解,並有助於未來腺甘酸相關藥物在臨床上的應用。

近幾年來有許多論文指出漢丁頓舞蹈症有代謝方面的問題、突變的Htt塊形會集結在肝臟,論文的第二部分主要在探討漢丁頓氏舞蹈症小鼠之尿素循環障礙之治療研究。以二個漢丁頓舞蹈症基因轉殖小鼠(R6/2和Hdh (CAG)150)為動物模型,首先我們發現R6/2和Hdh (CAG)150小鼠的血液胺基酸異常,citrulline的含量是野生鼠的2~3倍。同時在血液中的胺質(ammonia)也較高,肝循環的相關酵素也不正常,極可能有尿素循環障礙。過高的胺質會造成神經元受損,這提供了漢丁頓氏舞蹈症的可能致病機轉。使用低蛋白食物以降低血液中的胺質,可以改善R6/2小鼠的運動失調現象,增加腦中BDNF的表現,減少肝臟Htt的塊形集結和提高chaperone蛋白質 (HSP27和70)的表現以改善Htt塊形的堆積及所引起的疾病症狀。另一方面C/EBP�捔鉯�因子會調節尿素循環中許多酵素的表現,我們也發現了Htt突變蛋白會破壞C/EBP�悕M它的共同因子CBP之共同作用功能、把C/EBP�悒]含入Htt的塊形、同時也會抑制C/EBP�扆穧]和蛋白的表現。對於漢丁頓氏舞蹈症,了解尿素循環障礙產生的原因及使用低蛋白食物來改善尿素循環障礙會是有潛力的一個治療方向。

論文的第三部分是以蛋白體技術ICAT來分析在漢丁頓氏舞蹈症中受到影響的蛋白質。紋狀體是漢丁頓氏舞蹈症中受損最嚴重的部位,因此我們利用ICAT來尋找有多少的紋狀體蛋白質受到突變漢丁頓蛋白的影響。ICAT試劑先對peptides進行同位素標記,可以在全部的proteome中快速且全方位尋找出目標蛋白質,再以質譜儀等儀器對蛋白質表現量的差異作定量分析,同時用NCBI 資料庫鑑定目標蛋白質的名稱及可能的功能。在兩次ICAT實驗共偵查到大約四百多個蛋白質,其中有62個蛋白質在兩次實驗中都有顯著差異。有16個蛋白質的表現在漢丁頓小鼠紋狀體中有上升的趨勢,另外46個蛋白質的表現則是有下降的趨勢。同時用西方墨點法確認了PKCb, ��-actin, FKBP12和14-3-3ς等4個蛋白質的表現在R6/2小鼠中確實是有下降的趨勢,與ICAT的結果是一致的。我們也發現了若提升14-3-3ς蛋白質的表現可減少Htt突變蛋白的堆積在ST14A細胞中。這些結果也說明了蛋白體ICAT是可靠的、精確的技術,同時若能了解這些蛋白質的功能,將可進一步探討漢丁頓氏舞蹈症的致病機制。
Huntington’s disease is a neurodegenerative disease resulting from a CAG (glutamine, Q) trinucleotide expansion in exon 1 of the Huntingtin (Htt) gene. The role of the striatum-enriched A2A adenosine receptor (A2A-R) in Huntington’s disease has attracted much attention lately. In the present study, we found that expression of mutant Htt with expanded poly(Q) significantly reduced the transcript levels of the endogenous A2A-R in PC12 cells and primary striatal neurons. Cotransfection of various promoter constructs of the A2A-R gene and an expression construct of poly(Q)-expanded Htt revealed that the Htt mutant suppressed the core promoter activity of the A2A-R gene. Stimulation of the A2A-R using CGS21680, forskolin, and a constitutively active cAMPresponse element-binding protein (CREB) mutant elevated the reduced promoter activity of the A2A-R gene by mutant Htt. Moreover, the effect of CGS was blocked by an A2A-R-selective antagonist (CSC), two inhibitors of protein kinase A, and two dominant negative mutants of (CREB). The protein kinase A/CREB pathway therefore is involved in regulating A2A-R promoter activity. Consistently, an atypical CRE site (TCCAGG) is located in the core promoter region of the A2A-R gene. Electrophoretic gel mobility shift assay and mutational inactivation further demonstrated the functional binding of CREB to the core promoter region and showed that expression of poly(Q) - expanded Htt abolished the binding of CREB to this site. Stimulation of the A2A-R restored the reduced CREB binding caused by the mutant and concurrently reduced mutant Htt aggregation. Collectively, the poly(Q)- expanded mutant Htt suppressed expression of the A2A-R by inhibiting its core promoter at least partially by preventing CREB binding.

In the second part of this thesis, about mutant Htt with expanded polyQ forms aggregates in the liver which are associated with the progress of HD. Using two different mouse models of HD (R6/2 and Hdh(CAG)150), we demonstrate that urea cycle deficiency characterized by hyperammonemia, elevated blood citrulline, and suppression of urea cycle enzymes is a prominent feature of HD. The resultant high level of blood ammonia is likely to cause ammonia toxicity in the brain and enhances the neurological deficit of HD. To strengthen this hypothesis, we show that two protein-restricted diets not only retarded hyperammonemia in R6/2 mice, also ameliorated the formation of Htt aggregates, the deterioration of motor coordination, the suppression of BDNF expression in the brain, the decreased expression of two protein chaperons (HSP27 and HSP70), and the reduced expression of two key enzymes of urea cycle (argininosuccinate synthetase and argininosucciniate lyase). Suppression of C/EBP��, a crucial transcription factor for the transcription of urea cycle enzymes, appears to mediate the urea cycle deficiency in R6/2 mice. Our data reveal that mutant Htt inhibits C/EBP�� at multiple levels including blocking the interaction between C/EBP�� and its cofactor (CBP), recruiting C/EBP�� into Htt aggregates, and reducing the gene expression of C/EBP��. Collectively, the urea cycle deficiency contributes significantly to the pathology of HD. Low protein diet and treatments aimed at reducing ammonia provide a new strategy to develop beneficial treatments for HD.

In the third part of this thesis, to identify proteins critical for the disease progression of HD, we applied the acid-cleavable isotope coded affinity tag (ICAT) technology to quantitatively determine changes in protein expression in the striatum of R6/2 mice. Striatal proteins from the HD and wildtype mice were labeled with the heavy and light forms of ICAT reagents, respectively, at their cysteine residues. The samples were trypsinized, uncovered by avidin-affinity chromatography, and analyzed by nanoLC-tandem mass spectrometry (MS/MS). Linear regression analyses were employed to improve the data quality and to uncover a high-confidence group of proteins with meaningful changes. In two independent ICAT experiments, we identified 441 cysteine-containing striatal proteins. Of which, ��66% (203 unique proteins) could be detected in both ICAT experiments. A total of 62 proteins with statistically significant changes were identified in the striatum of HD mice. Downregulation of four proteins (PKC��, ��-actin, FKBP12 and 14-3-3ς) revealed by ICAT was further verified by Western blot analyses. Moreover, elevated expression of 14-3-3ς effectively reduced Htt aggregates in a striatal cell line, supporting a potential functional role of 14-3-3ς in HD. The results indicate that using a well-defined protocol for data analysis, large scale comparison of protein expression by ICATs can be accurate, and will provide valuable clues to identify proteins critical for pathophysiological functions.
Contents ……………………………………………………………….I
List of Tables …………………………………………………………..IV
List of Figures …………………………………………………………..V
List of Abbreviations…………………………………………………VIII
Chinese Abstract………………………………………………………IX
English Abstract………………………………………………………..XI
Introduction ……………………………………………………………..1
Materials and Methods…………………………………………………7
Results …………………………………………………………………23
1.1 Expression of mutant Htt in primary striatal neurons and PC12 cells
led to the formation of Htt aggregates…………………………......23
1.2 Expression of A2AR and its signaling effectors in the striatum of a
R6/2 mice……………………………………………………......24
1.3 Expression of mutant Htt reduced the expression of endogenous
A2AR gene, but not that of Bcl-2 gene, in PC12 cells and
primary striatal neurons……………………………….................25
1.4 Expression of mutant Htt suppressed the activity of A2AR promoter
in PC12 cells and primary striatal neurons………………………...25
1.5 Stimulation of A2AR reversed the A2AR promoter activity reduced
by mutant Htt in PC12 cells…………………………………….....26
1.6 Atypical CRE site is located at the core promoter region of the
A2A-R………......................................................................... 27
1.7 The functional CRE site was critical for A2A-R promoter activity…….29
1.8 Mutant Htt interfered with the binding of CREB to the atypical CRE
site of the A2A-R gene…………………………………………….30
1.9 Mutant Htt reduced the activation of CREB and the expression
of CBP……………………………………………………………31
1.10 BTEB3 appeared to be an important transcription factor of the
core promoter of the A2A-R gene…………………………….........31
2.1 Urea cycle deficiency contributes to the disease progression of
HD……………………………………………………………….33
2.2 Suppression of C/EBP�� by mutant Htt leads to urea cycle
deficiency in HD…………………………………………………..36
2.3 Blood citrulline is a diagnostic marker in the treatment of urea
cycle deficiency in HD…………………………………………….40
2.4 The impairment of energy metabolism contribute to
neurodegenerative processes in HD………………………………40
3.1 The ICAT approach to quantify and analysis of the striatal proteins
of HD…………………………………………………………….41
3.2 Downregulation of four proteins (PKC ��, ��-actin, FKBP12 and
14-3-3ς) revealed by ICAT………………………………………..42

Discussion……………………………………………………………...44
1.1 Summary of Part-I………………………………………………..44
1.2 The functional CRE site was critical for A2A-R promoter activity and contributed to suppression of the A2A-R gene by mutant Htt………..44
1.3 The PKA/CREB pathway played a critical role in mediating the protective effect of A2A-R for HD…………………………………..46
2.1 Summary of Part-II………………………………………………..47
2.2 Hyperammonemia symptom plays an novel role in the disease progression of HD………………………………………………...48
2.3 The suppression of urea cycle enzymes is a prominent feature of
HD……………………………………………………………….49
2.4 C/EBP�� played a critical role in mediating the effect of urea cycle enzymes and contributed to suppression of the urea cycle enzymes
by mutant Htt……………………………………………………..50
2.5 Deficits in metabolic profile uncover novel pathologies of HD………51
3.1 Summary of Part-III……………………………………………….52
3.2 Proteins identified in the present study might play functional roles in
the pathogenesis of HD…………………………………………..52

Perspectives…………………………………………………………...55
References …………………………………………………………….56
Tables and figures……………………………………………………..70
Appendices……………………………………………………………161
Paper and manuscript……………………………………………….166
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