聚麩醯胺擴增所造成的神經退化性疾病是由於其致病基因的外引子不正常的CAG三核苷酸擴增導致。在細胞及分子的層次上，其致病機轉雖尚未完全釐清，但由近幾年的研究發現轉錄失調為這類疾病的主要原因之一，一般認為聚麩醯胺造成轉錄失調有兩種方式：1.干擾轉錄因子間的交互作用； 2. 把轉錄因子捕捉在包涵體中使其無法作用。TATA box binding protein (TBP)為細胞內重要的轉錄因子，當其胺基端聚麩醯胺擴增時會導致第十七型脊髓小腦共濟失調症 (SCA17)。本研究的主要目的即是利用第十七型脊髓小腦共濟失調症果蠅模式株，來探討異常聚麩醯胺擴增的TBP蛋白質與相關因子對病理症狀有何影響，並釐清TBP在聚麩醯胺擴增造成的神經退化性疾病所伴演的角色。我們研究發現TBP功能為果蠅發育所必需，當其功能缺失時果蠅無法孵化，降低TBP表現或將其功能在特定組織致默後會造成複眼感光細胞退化，運動行為缺陷及壽命減短等性狀，第十七型小腦萎縮症果蠅疾病模式的性狀也會因其功能的缺失而更加嚴重，相對地增加TBP的表現則能有效地改善上述退化及行為等性狀，顯見TBP功能的減少為第十七型脊髓小腦共濟失調症致病機轉的一環。此外由於研究指出High Mobility Group (HMG) 的蛋白質會抑制TBP的轉錄作用，我們也籍由HMG 的同源基因- HmgD來干擾TBP，當HmgD大量表現時果蠅複眼感光細胞確有退化的現象，SCA17果蠅模式動物在此背景下也會加劇其病徵。

Polyglutamine (polyQ) diseases are a specific group of hereditary neurodegenerative diseases caused by expansion of CAG trinucleotide repeats in the exon of the corresponding gene. The pathological mechanism underlying polyglutamine mediated neurodegenerative diseases has not been fully elucidated in cellular and molecular level. Recently advancement in unraveling the pathogenic mechanism of polyQ mediated neurodegenerative diseases has pointed that transcription dysregulation is one of the major factors that results in death of neurons. It is generally accepted that polyQ causes transcription dysfunction in two ways: 1. polyQ disrupts the normal interaction of transcription factor; 2. many transcription factors were sequestered in polyQ containing inclusions. TATA Box binding protein (TBP) is a general transcription factor that is required for transcription of all three types of RNA polymerases in cell. It has been reported that SCA17 has been attributed to the polyQ expansion at amino terminal of TBP. The major goal of my study is to study how the abnormal TBP leads to SCA17 pathogenesis using Drosophila as model system, and dissect the role of TBP in polyQ mediated neurodegenerative diseases. We have found that TBP is essential for early embryogenesis of Drosophila. Fly embryos can not hatch in the absence of TBP. Reducing the function of TBP in certain tissues by RNA interference causes various phenotypes, including degeneration of photoreceptor cells, defect in mobility and pre-mature death. And pathological phenotype of SCA17 is enhanced in the loss-of-function of TBP. Conversely, increasing the expression of TBP would alleviated abovementioned disorders, suggesting loss-of-function of TBP is involved in the pathogenesis of SCA17, In addition, previous study has show HMG binds to TBP and suppresses TBP mediated transcription. We have found ectopic HmgD causes retinal degeneration in fly. And co-expression of both mutant TBP and HmgD leads more severe defects.

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