研究生: |
王品蓉 Pin-Rong Wang |
---|---|
論文名稱: |
熱休克蛋白過度表現及氧化壓力對SCA17細胞模式影響之研究 The Effects of HSPs Overexpression and Oxidative Stress in SCA17 Cell Model |
指導教授: |
李桂楨
Lee, Guey-Jen |
學位類別: |
碩士 Master |
系所名稱: |
生命科學系 Department of Life Science |
論文出版年: | 2009 |
畢業學年度: | 97 |
語文別: | 中文 |
論文頁數: | 73 |
中文關鍵詞: | 第十七型脊髓小腦運動失調症 、熱休克蛋白 、氧化壓力 |
英文關鍵詞: | SCA17, heat shock protein, oxidative stress |
論文種類: | 學術論文 |
相關次數: | 點閱:185 下載:5 |
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脊髓小腦運動失調症(spinocerebellar ataxias,簡稱SCAs)為體染色體顯性遺傳的神經退化性疾病,有超過28種的亞型。其中的遺傳性第十七型脊髓小腦運動失調症(SCA17)與染色體6q27位置TATA binding protein (TBP)基因的CAG三核苷重複擴增相關。突變的TBP蛋白具有延長的聚麩醯胺(polyQ)片段,可能導致蛋白質結構錯誤摺疊及聚集,而polyQ擴增造成的氧化壓力與疾病形成有關。當細胞處於氧化壓力下,會提升熱休克蛋白的表現,如HSPA5、HSPA8和HSPB1等監護蛋白(chaperones),以便抵抗氧化壓力所造成的傷害。監護蛋白可經由穩定錯誤摺疊蛋白的結構,降低聚集的生成,來緩和polyQ突變蛋白的毒性。藉由熱休克蛋白和氧化壓力與SCA17的關連性做探討,我們可以更瞭解SCA17的致病機轉,有助於疾病的改善或治療策略的發展。藉誘導式細胞模式的建立,本篇研究結果顯示擴增polyQ的TBP蛋白聚集在細胞核中,且細胞週期呈現較高的sub G1%。表現擴增polyQ的TBP使細胞活性氧分子產量增加,且對staurosporine處理的敏感度提升及缺血清的耐受度下降。短暫表現TBP的細胞模式顯示,HSPA5、HSPA8和HSPB1的過度表現可以降低聚集的生成。
Autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders involving progressive degeneration of the cerebellum, brainstem, and spinal tract. More than 28 subtypes have been reported. SCA17 is caused by an expanded polyglutamine (polyQ) in a general transcription initiation factor, the TATA-box binding protein (TBP). The mutated TBP with polyQ expansion causes a conformational change to promote misfolding and aggregation. Futhermore, a polyQ mutation can induce reactive oxygen species (ROS) that directly contribute to cell death. During oxidative stress, synthesis of several heat shock proteins (such as HSPA5, HSPA8 and HSPB1 chaperones) increase to protect cells against oxidative stress. Chaperones may modulate polyQ protein toxicity by stabilizing the misfolded conformation to reduce aggregate formation. Investigation of chaperones and oxidative stress associated with SCA17 may not only contribute to the understanding of molecular mechanism of the disease but also provide therapeutic strategy to slow down the disease progression. By establishing stably induced cell model, the study results revealed that TBP with expanded polyQ formed nuclear aggregates with significant increase in sub G1 phase of cell cycle. Cells expressed polyQ-expanded TBP display increased ROS production and increased sensitivity to staurosporine treatment and serum deprivation. Using transient cell model, HSPA5, HSPA8 and HSPB1 overexpression can reduce aggregate formation.
李麗卿(2009)。第十七型脊髓小腦共濟失調症致病機轉:伴隨蛋白的保護功能與TATA結合蛋白CAG三核苷重複擴增造成不正常蛋白質折疊之研究。國立台灣師範大學生命科學系九十七學年度博士論文。
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