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研究生: 林書安
Lin, Shu-An
論文名稱: 針對第三型小腦萎縮症探討神經發炎致病機制與具潛力的治療策略
Pathomechanism characterization and potential therapeutics identification for SCA3 targeting neuroinflammation
指導教授: 李桂楨
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: 2019
畢業學年度: 107
語文別: 中文
論文頁數: 80
中文關鍵詞: 第三型小腦萎縮症多麩醯胺微膠細胞神經發炎介白素-1β
英文關鍵詞: Spinocerebellar ataxia type 3, polyglutamine, microglia, neuroinflammation, IL-1β
DOI URL: http://doi.org/10.6345/NTNU201901042
論文種類: 學術論文
相關次數: 點閱:122下載:0
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  • 多麩醯胺(PolyQ)介導的脊髓小腦共濟失調症(SCA)是由於基因編碼序列中,擴增CAG的重複突變所引起。PolyQ蛋白的錯誤折疊和聚集導致毒性增加,是發病機制的核心,並且伴隨著活性氧化物(ROS)的產生和細胞毒性的增加。氧化壓力會誘發發炎反應,且發炎過程會更進一步造成ROS提升與降低細胞的抗氧化能力。在SCA中,第三型脊髓小腦共濟失調症(SCA3)是脊髓小腦共濟失調症中最常見的一型,在台灣所有病例中約佔50%。先前的文獻發現,在SCA3患者橋腦中,出現星狀細胞與微膠細胞活化,顯示發炎過程參與了疾病的致病機制。本研究首先使用小鼠BV-2和人類HMC3微膠細胞(Microglia),評估四種具潛力化合物NC009-1、AM404、VB-037、LM-031的抗發炎能力。在脂多醣(LPS)及γ型干擾素(IFN-γ)活化的小鼠微膠細胞中,四種化合物皆抑制釋放至培養基的一氧化氮(NO)量,顯示具抗發炎活性。在IFN-γ活化的人類微膠細胞中,四種化合物亦皆能抑制釋放至培養基的NO、介白素-1β (IL-1β)、腫瘤壞死因子-α (TNF-α)、介白素-6 (IL-6)量,並降低細胞中CD68的表現量,顯示其抗發炎活性。為了評估上述化合物於PolyQ SCA的治療潛力,建立了可誘導表現SCA3 ATXN3/Q14~75-GFP並以視黃酸(Retinoic acid)誘導神經分化的SH-SY5Y細胞。待測化合物前處理表現ATXN3/Q75-GFP且神經分化的SH-SY5Y細胞,可以促進神經突生長並減少聚集。視黃酸誘導神經分化及表現ATXN3/Q75-GFP的SH-SY5Y細胞,給予來自LPS及IFN-γ活化的小鼠微膠細胞或IFN-γ刺激的人類微膠細胞的制約培養液(Conditioned medium)的發炎刺激後,增加的凋亡蛋白酶1 (Caspase 1)活性與乳酸脫氫酶(LDH)釋放量,可透過前處理NC009-1、AM404、VB-037、LM-031後而緩解。此外,上述ATXN3/Q75-GFP的SH-SY5Y細胞給予人類微膠細胞制約培養液的發炎刺激後,AM404與LM-031可抑制活性氧化物的上升,NC009-1、AM404、LM-031可以提升神經突生長,NC009-1、VB-037、LM-031可減少PolyQ聚集。接著檢測IL-1發炎相關路徑,發現NC009-1可抑制IκBα-NF-κB路徑的活化,AM404可抑制JNK-JUN路徑的活化,VB-037可抑制JNK-JUN及P38-STAT1路徑的活化,LM-031可抑制IκBα-NF-κB及P38-STAT1路徑的活化。此研究提供新的觀點,有助於第三型小腦萎縮症發炎機制的探討。

    Polyglutamine (polyQ)-mediated spinocerebellar ataxias (SCA) are caused by mutant genes with expanded CAG repeats encoding polyQ tracts. The misfolding and aggregation of polyQ proteins result in a gain of toxicity that are central to pathogenesis and a concomitant increase in reactive oxygen species (ROS) levels and cellular toxicity. Inflammation is one of the manifestations of oxidative stress and inflammatory process may further induce ROS and reduce cellular antioxidant capacity. Among SCA, SCA type 3 (SCA3) is the most common diagnosis worldwide, accounting for nearly 50% of all cases in Taiwanese. Increased numbers of reactive astrocytes and microglia have been found in SCA3 pons, suggesting the involvement of inflammatory process in the disease pathogenesis. In this study, the anti-inflammatory potentials of NC009-1, AM404, VB-037, and LM-031 were evaluated firstly by using mouse BV-2 and human HMC3 microglial cells. In lipopolysaccharide (LPS) and interferon-γ (IFN-γ) activated mouse BV-2 cells, all four compounds displayed anti-inflammatory activity by suppressing nitric oxide (NO) production in cultured medium. In IFN-γ-activated human HMC3 cells, the test compounds also displayed anti-inflammatory activity by suppressing NO, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) production in cultured medium and CD68 expression in cells. To assess the therapeutic potentials of test compounds, retinoic acid differentiated human SH-SY5Y cells with inducible ATXN3/Q14~75-GFP expression and polyQ-length dependent aggregation were established, and pretreatment of test compounds promoted neurite outgrowth and reduced polyQ aggragation. In retinoic acid-differentiated ATXN3/Q75-expressing SH-SY5Y cells inflamed with LPS- and IFN-γ-primed BV-2 or IFN-γ-primed HMC3 conditioned medium, increased caspase 1 activity and lactate dehydrogenase (LDH) release were mitigated by the treatment with NC009-1, AM404, VB-037, and LM-031. In addition, AM404 and LM-031 reduced mutant polyQ-associated reactive oxygen species, NC009-1, AM404, and LM-031 promoted neurite outgrowth, and NC009-1, VB-037, and LM-031 reduced polyQ aggregation in ATXN3/Q75 SH-SY5Y cells stimulated with IFN-γ-primed HMC3 conditioned medium. Examination of IL-1β-mediated pathways in inflamed ATXN3/Q75 SH-SY5Y cells revealed that NC009-1 downregulated IκBα-NF-κB pathway, AM404 downregulated JNK-JUN pathway, VB-037 downregulated JNK-JUN and P38-STAT1 pathways, and LM-031 downregulated IκBα-NF-κB and P38-STAT1 pathways. This study offers new viewpoints to explore the mechanisms of inflammation in spinocerebellar ataxia type 3.

    目錄 i 圖表次 v 摘要 vi 英文摘要 viii 壹、緒論 1 一、脊髓小腦共濟失調症 1 二、第三型脊髓小腦共濟失調症 2 三、神經發炎反應 2 四、介白素-1β和介白素-6中介的發炎路徑 4 五、神經發炎與第三型脊髓小腦共濟失調症的關聯 6 六、潛力化合物N009-1、AM404、VB-037、LM-031 7 貳、研究目的 9 參、研究材料與方法 10 一、誘導式SCA3細胞株建立 10 二、細胞培養與繼代 11 三、化合物的里賓斯基五規則、極性表面積及血腦屏障通透性預測 11 四、DPPH自由基清除能力測定 12 五、化合物細胞毒性檢測 12 六、NO釋放量測試 13 七、免疫細胞化學染色 14 八、細胞處理、蛋白配製及西方墨點分析 14 九、酵素免疫分析 17 十、ATXN3/Q14~75-GFP SH-SY5Y神經突生長與聚集分析 18 十一、前處理化合物於ATXN3/Q75-GFP SH-SY5Y的聚集與神經突生長分析 18 十二、發炎性ATXN3/Q75-GFP SH-SY5Y細胞存活率分析 19 十三、發炎性ATXN3/Q75-GFP SH-SY5Y細胞乳酸脫氫酶(LDH)分析 19 十四、發炎性ATXN3/Q75-GFP SH-SY5Y細胞凋亡蛋白酶1(Caspase 1)活性分析 20 十五、前處理化合物於發炎性ATXN3/Q75-GFP SH-SY5Y的聚集與神經突生長分析 20 十六、發炎性ATXN3/Q75-GFP SH-SY5Y細胞活性氧化物分析 21 十七、統計分析 21 肆、結果 22 一、化合物溶解度及里賓斯基五規則/極性表面積/血腦屏障通透性預測 22 二、化合物自由基清除效力分析 23 三、化合物細胞毒性分析 23 四、以LPS及IFN-γ活化BV-2細胞檢測化合物抗發炎效果 24 五、以IFN-γ活化HMC3細胞檢測化合物抗發炎效果 25 六、誘導式ATXN3/Q14~75-GFP SH-SY5Y細胞 26 七、ATXN3/Q14~75-GFP SH-SY5Y細胞聚集與神經突生長分析 27 八、化合物對ATXN3/Q75-GFP SH-SY5Y細胞聚集與神經突生長分析 28 九、化合物對BV-2制約培養液刺激SCA3細胞發炎的神經保護作用 29 十、化合物對HMC3制約培養液刺激SCA3細胞發炎的神經保護作用 30 十一、化合物對HMC3制約培養液刺激SCA3細胞發炎的活性氧化物、具及與神經突生長分析 31 十二、化合物對HMC3制約培養液刺激SCA3細胞發炎神經保護機轉路徑 33 伍、討論 35 一、第三型脊髓小腦萎縮症致病機制與毒性片段假說 35 二、微膠細胞與神經發炎反應 36 三、潛力化合物生物利用性與神經保護效果 40 四、潛力化合物在發炎模式中達神經保護的機轉路徑 42 伍、結論及未來研究方向 45 陸、參考文獻 46 柒、附錄圖表 58

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