臺灣博碩士論文加值系統

漢丁頓氏舞蹈症 (HD) 是一體染色體顯性遺傳的神經退化性疾病，導因是Huntingtin (Htt) 基因的第一表現子 (exon 1) 上，CAG三核甘酸序列重覆 (CAG trinucleotide repeats) 的數目有異常的表現。我們運用HD的轉基因老鼠模型 (R6/2)，而此老鼠模型可能是因脂肪組織發生損害和肌肉體積的喪失而產生高血糖和漸進性體重減輕這兩種主要的症狀，這也有助於提供HD的病理學。在目前我們運用HD的轉基因老鼠模型 (R6/2) 上，證明在皮下及腹部的白色脂肪脂質生成的情形有顯著減少，且發現不正常新陳代謝現象如漸進性體重下降及高血糖。相較我們長期給予過氧化小體增生活化受體 (PPARγ) 的活性劑：thiazolidinedione (TZD) 後，產生包括改善漸進性體重下降和改變脂質生成的有益結果。在R6/2 老鼠模型方面，在長期給予TZD後，針對於R6/2小鼠不同組織層的白色脂肪予以以西方點墨法 (western blot) 證明TZD會增加第四型葡萄糖攜帶蛋白 (Glucose transporter type 4, GLUT4) 和蛋白激�、 (AKT/PKB) 的表現。同時我們也在細胞模型方面，運用C2C12 (肌肉細胞株) 轉殖入Htt (109Q) 經由RGZ分別處理24或48小時後，進行螢光免疫染色也觀察到RGZ能改善細胞內堆疊的形成，並且運用粒線體活化功能測定(mitochondrial function mass measurements) 和冷光蛋白活性分析 (luciferase assay) 的實驗，測定出在經由RGZ處理的C2C12細胞株，可以透過引起PPARγ活化且進而增強粒線體的表現。目前初步證明TZD會對周邊組織形成保護作用，最重要的是減少堆疊 (aggregate) 的形成，所以TZD可顯著的透過減緩異常的Htt蛋白堆疊對PPARγ的攔阻作用，並促進加強保護PPARγ的調控機制。總體而言，我們可以運用TZD治療HD所產生的新陳代謝併發症及延緩HD的發生。

Huntington's disease (HD) is an autosomal dominant hereditary neurodegenerative disease caused by a CAG trinucleotide repeats exceptional expansion of exon 1 of the Huntingtin (Htt) gene. In the present study, I used a transgenic mouse model (R6/2) of HD which exhibited high levels of blood glucose and progressive reduction in body weight. Both symptoms are two major symptoms of HD, and which might be resulted from damage of adipose tissues and loss of muscle bulk. We demonstrate herein that the alterations in lipogenesis of markedly decreased subcutaneous and abdominal white adipose tissue (WAT) and abnormal metabolic profiles such as progressive body weight lost and hyperglycemia. Chronic treatment with an agonist thiazolidinedione (TZD) of the peroxisome proliferator-activated receptor-γ (PPARγ) resulted in beneficial effects including improvements in progressive weight lost and elevated lipogenesis. Chronic treatment with TZD were further evaluated for metabolic-specific differences in the WAT of R6/2 mice. In addition, western blot analyses revealed that chronic TZD treatment increase expression of Glucose transporter type 4 (GLUT4) and protein kinases B (AKT/PKB). While in vitro that C2C12 (a muscle cell line) were transfected with Htt (109Q) and treatment with RGZ for 24, 48 hours. As shown by immunocytochemistry staining, RGZ also ameliorated intracellular aggregate formation. RGZ treatment induced PPARγ activation in C2C12 cell with mitochondrial function mass measurements. Preliminary data demonstrates that a protective role of TZD in the peripheral tissue. Most importantly, to reduce aggregate formation, TZD markedly slowed the hijacking of PPARγ by mutated Htt aggregates and further strengthened the PPARγ-mediated protective effects of drug (i.e., TZD). Collectively, we report that a TZD used for metabolic syndromes might be used to treat HD and delay the onset of HD.

目錄……………………………………………………………………I
圖、表目錄……………………………………………………………III
Abstract………………………………………………………………IV
中文摘要………………………………………………………………VI
第一章 緒論 …………………………………………………………1
(一) 漢丁頓氏舞蹈症 (Huntington’s disease, HD) 與CAG
三核�˙觸妤`重複序列導致的神經退化疾病 ……………1
(二) HD導致神經細胞死亡的機制 ………………………………2
(三) HD所誘發的代謝障礙 ………………………………………4
(四) Thiazolidinedione (TZD) 對脂肪及肌肉組織新陳代謝
的影響 ………………………………………………………7
第二章 實驗研究目的 ………………………………………………8
第三章 實驗材料與方法 ……………………………………………9
第一節 實驗動物 …………………………………………………9
第二節 蛋白質定量 ………………………………………………10
第三節 SDS-PAGE及西方點墨法 (Western Blot)………………11
第四節 組織染色法 (Histochemistry Stain)…………………13
第五節 載體 (Constructs)………………………………………14
第六節 質體DNA (Plasmid DNA) 之萃取 ………………………14
第七節 細胞培養 …………………………………………………16
第八節 細胞免疫染色法 (Immunocytochemistry) ……………16
第九節 粒腺體功能測定 (Mitochondrial Function Mass
Measurements)……………………………………………18
第十節 冷光蛋白活性分析 (Luciferase Assay)………………19
第十一節 本論文實驗耗材與試劑來源 …………………………21
第四章 實驗結果 ……………………………………………………22
第一節 在長期給予TZD處理後對R6/2體重與脂肪組織重量的
改變 ………………………………………………………22
第二節 在長期給予TZD處理後對R6/2血液中葡萄糖表現的變
化 …………………………………………………………23
第三節 TZD處理後對R6/2白色脂肪內調控葡萄糖吸收相關因
子的影響 …………………………………………………23
第四節 在長期給予TZD處理後對R6/2肌肉組織型態的影響……24
第五節 觀察給予RGZ處理後，對於表現Htt基因的C2C12細胞
所產生的影響 ……………………………………………25
第五章 討論 …………………………………………………………27
第一節 在長期給予TZD處理後對R6/2體重與脂肪組織重量的
改變 ………………………………………………………27
第二節 在長期給予TZD處理後對R6/2血液中葡萄糖表現的變
化 …………………………………………………………28
第三節 TZD處理後對R6/2白色脂肪內調控葡萄糖吸收相關因
子的影響 …………………………………………………28
第四節 在長期給予TZD處理後對R6/2肌肉組織型態的影響……30
第五節 觀察給予RGZ處理後，對於表現Htt基因的C2C12細
胞所產生的影響 …………………………………………31
第六章 未來展望 ……………………………………………………34
第七章 圖、表及說明 ………………………………………………35

表目錄
表1. 在長期給予TZD處理後對於皮下白色脂肪重量的影響……36
表2. 在長期給予TZD處理後對於腹部白色脂肪重量的影響……37
表3. 在長期給予TZD處理後對於棕色脂肪重量的影響…………38

圖目錄
圖1. 在長期給予TZD處理後脂肪組織型態的表現………………39
圖2. 在長期給予TZD處理後對皮下與腹部白色脂肪組織中
GLUT4蛋白質含量的影響……………………………………41
圖3. 在長期給予TZD處理後對皮下白色脂肪組織中AKT蛋白
質含量的影響 ………………………………………………43
圖4. 在長期給予TZD處理後肌肉組織細胞型態的表現…………44
圖5. C2C12細胞在轉殖Htt基因後給予RGZ處理24小時，觀察
細胞內產生異常Htt蛋白堆疊的情況………………………47
圖6. C2C12細胞在轉殖Htt基因後給予RGZ處理24小時，觀察
細胞內異常的Htt蛋白堆疊對於PPARγ蛋白質的表現影
響 ……………………………………………………………49
圖7. 在C2C12細胞株在轉殖Htt基因，給予RGZ、GW9662處理
24小時後，觀察粒線體的活化功能 ………………………51
圖8. 在C2C12細胞株在轉殖Htt基因，給予RGZ、GW9662處理
48小時後，觀察粒線體的活化功能 ………………………54
圖9. 在C2C12細胞株在轉殖Htt基因，給予RGZ處理24小時後
，觀察PPARγ promoter的活化表現 ………………………57
第八章 參考資料 ……………………………………………………58
附錄……………………………………………………………………70
補充資料………………………………………………………………75
附圖 1. 在長期給予TZD處理後對R6/2 mice體重的影響………76
附圖 2..在長期給予TZD處理後對R6/2 mice血糖的影響………77

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