TBP功能缺失參與阿茲海默氏症果蠅模式中之類澱粉蛋白毒性

Abstract

蛋白質不正常的折疊聚集是許多退化性神經疾病的指標之一，其中也包括阿茲海默症。目前已知阿茲海默症常見的致病原因有二，其一為細胞外β類澱粉蛋白質堆積；另一病徵則為Tau蛋白質堆積所形成的神經纖維狀糾結並造成漸進性的腦皮層萎縮。不正常的蛋白質堆積也是其他退化性神經疾病的常見特徵之一，包括遺傳性的多麩醯胺酸疾病亨丁頓舞蹈症和小腦萎縮症。在上述的這些退化性疾病當中皆有一定比例的不可溶性的轉錄因子TATA box binding protein(TBP)，這些包含麩醯胺酸的不正常折疊堆積也可能是造成阿茲海默症的原因之一。先前已有資料顯示正常野生型的TBP和β類澱粉蛋白質以及Tau蛋白質在阿茲海默症的病人腦中堆積，根據此一證據我們進一步在果蠅模式下實驗證實β類澱粉蛋白質可能透過影響TBP的結合功能或是轉錄功能進而成阿茲海默症的成因之一。我們的研究發現大量表現β類澱粉蛋白質在果蠅的特定組織部位造成許多病理上的症狀，包括複眼細胞的退化、運動行為缺陷及壽命減短等現象；相反地增加TBP的表現則能有效的改善上述退化及行為等性狀，而抑制果蠅內生性的TBP蛋白則使得這些性狀更加嚴重。另外，運用EMSA的方式證實類澱粉蛋白濃度提高造成了TBP對TATA DNA的結合力下降。在果蠅的腦中我們也發現隨著時間上升類澱粉蛋白聚集也因共同表現TBP而減少了聚集的數量，顯示出正常功能的TBP能夠有效的減緩類澱粉蛋白造成的毒性。我們的研究結果顯示出TBP參與阿茲海默症果蠅致病機轉。

Protein aggregation is a pathological hallmark of many neurodegenerative diseases, including Alzheimer’s disease (AD). ADis characterized by extra cellular β-amyloid deposition, Tau-containing neurofibrillary tangles (NFTs) and progressive cortical atrophy. Abnormal protein accumulation is also a common feature of other late onset neurodegenerative diseases, including the heritable polyglutamine (polyQ) disorders such as Huntington disease (HD) and the spinocerebellar ataxias (SCAs). Since TBP is insoluble in the brain AD patients, the accumulation or misfolding of this polyQ containing protein may be acontributing factor in AD. Previous study has demonstrated that wild type length TATA box binding protein(TBP),β-amyloidand Tau-containing NFTs accumulatein AD patient brains. It was hypothesized that TBP inactivation may contribute to the pathogenesis of AD, in which the transactivation activity or binding ability of TBP may be influenced by β-amyloid deposition. In my study. Overexpression ofβ-amyloidin certain tissue causes various phenotypes, including degeneration of photoreceptor cells, defect in mobility and shorten lifespan. The pathological phenotypes of AD is enhanced in the loss-of-function of TBP flies. In contrast, increasing the expression of TBP ameliorates the abovementioned disorders. These observations suggest that loss-of-function of TBP is involved in the pathogenesis of AD. Immunostaining results showed that TBP accumulated and co-localized with amyloid-containing plaque. In addition, we demonstrated that the increase of Aβ-42 concentration was accompanied with the decrease of TBP-DNA bind ability in vitro. Furthermore, overexpression of TBP reduced and delayed deposits in adult brain. In sum, my study demonstrates that deactivation of TBP contributes to the pathogenesis of AD, which provide new insight into the pathogenesis of AD.