系統識別號 U0026-3007201515164500
論文名稱(中文) 新穎蛋白在額顳葉退化症中參與自噬性清除TDP-43包含體的研究
論文名稱(英文) Autophagic clearance of TDP-43 inclusions is mediated by a novel protein in FTLD-U
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 徐唯恩
研究生(英文) Wei-En Hsu
學號 S96021074
學位類別 碩士
語文別 英文
論文頁數 51頁
口試委員 指導教授-蔡坤哲
中文關鍵字 額顳葉退化症  自噬 
英文關鍵字 Frontotemporal lobar degeneration  autophagy 
中文摘要 額顳葉退化症(FTLD)是一種神經退化性疾病,特徵為在病程中因為核內和核內包含體的出現導致腦部額葉/顳葉神經元的損失,進而使病人產生行為/語言功能和運動能力的障礙。 TDP-43已被確定為具有泛素包含體之額顳葉退化症(FTLD-U)中主要的疾病蛋白;在病理情況下,TDP-43通常被錯置到細胞質中,形成具有神經毒性的包含體。自噬作用是細胞在清理錯誤折疊或聚集的蛋白質的過程。在以前的研究中,自噬活化劑可減緩FTLD-U小鼠模型的發病;而本研究重點之新穎蛋白已被發現在阿茨海默氏症(AD)中可以阻止β-澱粉狀蛋白積累成斑塊。因此,在本文中,我們研究此新穎蛋白是否可以通過調節自噬過程去降解TDP-43包含體,並對FTLD-U產生神經保護作用。首先,此蛋白在FTLD-U小鼠中的失調顯示其可能在FTLD-U病程中扮演重要的角色。第二,我們發現此蛋白會與自噬相關蛋白ATF4產生交互作用,從而提出此新穎蛋白可能在參與在調節自噬作用的假說。在FTLD-U細胞模型中,我們確實發現此蛋白可誘導自噬作用使得TDP-43包含體被清除。因此,我們建立了特別在前腦過度表達此蛋白的FTLD-U小鼠模型。與FTLD-U小鼠相比,我們觀察到此雙轉殖基因小鼠在行為表現上的改善和TDP-43包含體的清除。綜合來看,自噬作用可以被本文研究之新穎蛋白誘導,並參與在清除病程中的TDP-43包含體,因此,其可能是在治療FTLD-U中的一個標靶。
英文摘要 Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease characterized by neuronal loss in frontal/temporal lobe of brain associated with cytoplasmic and nuclear inclusions, resulting in patient’s behavior/language dysfunction and motor deficit. TDP-43 has been identified as the major disease protein for FTLD with ubiquitin-positive inclusions (FTLD-U). Under pathological condition, TDP-43 mislocalizes into cytoplasm and forms neurotoxic aggregations. Autophagy is a self-degradative process in clearing misfolded or aggregated proteins. In previous studies, autophagy activators can alleviate the pathogenesis in FTLD-U mouse model and the novel protein represent in this thesis has beneficial effects in Alzheimer’s disease (AD) by preventing beta-amyloids to accumulate into the plaques. Hence, we intend to investigate whether this protein can provide neuroprotective effects in FTLD-U by modulating autophagic process for degrading TDP-43 inclusions. First, the dysregulation of the protein we focused in FTLD-U mice indicated this protein might play a role in FTLD-U pathology. Second, the interaction of the novel protein with autophagy-related protein ATF4 leaded to the hypothesis that it might involve in regulating autophagy. The clearance of TDP-43 inclusions and the induction of autophagy by overexpressing this protein were both observed in FTLD-U cell model. Therefore, we generated a mouse model which forebrain-specifically overexpressed both TDP-43 and the protein of our interest. Comparing with FTLD-U mouse, autophagy was induced in this double transgenic mice, resulting in the rescue of behavioral performances and the clearance of TDP-43 inclusions. Taken together, autophagy can be induced by this novel protein and take part in the clearance of TDP-43 inclusions, thus, it may be a therapeutic target in rescuing the pathological phenotype of FTLD-U.
論文目次 中文摘要 i
Abstract ii
Acknowledgement iii
Contents v
Background 1
Materials and Methods 11
Results 18
Discussion 24
References 27
Tables and Figure Legends 41
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