脊髓小腦萎縮症第十七型是由於 TATA-box binding protein (TBP) 基因外引子上CAG三核苷酸異常擴增所導致。TBP普遍且廣泛表現在所有型態的細胞，但其N端聚麸醯胺的擴增造成的病理徵狀卻只出現在小腦、皮質等中樞神經。前人的研究顯示人類High mobility group box 1 (HMGB1)和果蠅Dorsal switch protein 1 (DSP1) 在結構上有高度同源性，並且在RNA聚合酶II轉錄上扮演抑制子的角色。HMGB1和DSP1能夠直接和TBP的N端麸醯胺豐富的區域結合，並和結合在TBP上的DNA形成穩定的三元複合體，分別藉由干擾TFIIB和TFIIA與TBP結合，抑制RNA聚合酶II轉錄的啟始階段。本研究的主要目的，在SCA3、SCA17以及HD疾病的果蠅模式下，探討HMGB1和DSP1和聚麸醯胺擴增的蛋白質間交互作用。我們推測，突變的聚麸醯胺蛋白直接和HMGB1結合，並把HMGB1隔離在核內包涵體(intranuclear inclusions)，而HMGB1的功能喪失，使得轉錄功能的喪失，使得活化轉錄功能的失調，導致細胞凋亡以及神經退化病徵。在研究中我們發現過度表現果蠅內生性DSP1干擾了正常的TBP的功能，而過度表現HMGB1則對TBP沒有影響，顯示DSP1和HMGB1雖然具有高度同源性，但在轉錄中扮演的角色不完全相同。另一方面，我們發現補充DSP1和HMGB1 可以顯著的減輕全長的TBP109Q，或是截斷型的聚麸醯胺蛋白如：TBP-109Q NTD、MJD-78Q和Htt-97Q所造成的神經退化。這意味著這些異常擴增的聚麸醯胺蛋白能夠直接與HMGB1作用，並將之隔離在蛋白質聚合體 (aggregates)，而HMGB1喪失的功能可能是聚麸醯胺疾病的致病的普遍原因之一。同時過度表現DSP1和HMGB1增加了和變異的聚麸醯胺蛋白結合的機會，也減少了聚麸醯胺蛋白捕捉其他轉錄因子的數量，使得部分失調的轉錄功能可以恢復。

Spinocerebellar ataxia type 17 (SCA17) is caused by expansion of CAG trinucleotide repeats in the exon TATA box-binding protein (TBP) gene. TBP is commonly and ubiquitously expressed in all cells of multiple cell organsisms due to its essential role in transcription. Nevertheless, the pathological phenotype, which resulted from mutant TBP, are mostly found in central nervous system (CNS), such as cerebellum and cortex. Previous studies showed that RNA polymerase II dependent transcriptional repressor, High mobility group box 1 (HMGB1), binds directly to polyQ rich domain of TBP and was sequested by expanded polyQ containing proteins, including HD and AT1, suggesting HMB box containing proteins play a role in polyQ mediated diseases. Additionally, p53 has also been shown to be a TBP binding protein and implicated in pathogenesis of SCA17 . Herein, we employed an established Drosophila model of SCA3, SCA17 and HD to investigate roles of two TBP interacting proteins HMGB1/DSP1 and p53 in the polyQ induced neurodgenerations. We find that loss of function of HMGB1 results in transcriptional dysfunction and leads to apoptosis and neurodegeneration. We further demostrate that overexpression of DSP1 but not HMGB1 in fly eyes interferes with wild-type and TBP54Q in significant level, suggesting different roles in transcription. On the other hand, complement of DSP1 and HMGB1 markedly ameliorates neurodegeneration caused by full-length TBP109Q and truncated polyQ protein, including TBP-109QNTD, MJD78Q, and Htt97Q. These data suggested that mutant polyQ proteins with expanded Q stretch directly interact with HMGB1 and sequestrate them into aggregates, increasing the possibility that HMGB1 loss of function involves in the pathologies of general polyQ protein diseases. In this study we showed that overexprssion of DSP1 and HMGB1 is likely to be a polyQ binding protein, and loss-of-function of DSP1/HMGB1 may play an important role in polyQ mediated diseases.

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