TBP 的功能缺失參與在Tauopathy 的致病機轉中
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2012
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前人的研究發現阿茲海默症患者腦中TATA box binding protein (TBP) 會與tau所形成的neurofibrillary tangles (NFTs) 共沉積在細胞質內，表示tauopathy 的致病機轉可能有一部份是透過影響TBP的正常功能而來。由於大部分基因的轉錄都需要TBP的參與，因此我們想知道轉錄缺失是否是tauopathy的致病原因之一，首先我們利用已建立表現正常人類tau蛋白的tauopathy模式果蠅進行藥物實驗，當 我們將tau蛋白表現在這些模式果蠅背甲上時，會造成其背甲剛毛數目的減少，但投以包括SAHA等的HDAC inhibitors藥物時，會降低tau蛋白過量表現所造成的背甲剛毛數量的減少，表示轉錄功能的缺失或許參與在tuaopathies的致病機轉中。我們的實驗結果發現在細胞模式下TBP會與NFTs共同沉積在細胞質內，且TBP促進轉錄的功能也會受到影響。為了在動物模式下也證明我們的實驗，我們創造了表現纖維化tau蛋白的模式果蠅，此種模式果蠅的壽命較野生型果蠅短 。同時我們也發現了這些轉基因果蠅內會表現不可溶的纖維化蛋白。為了證明TBP功能缺失也會發生在我們的模式果蠅中，我們發現 TBP在轉基因果蠅腦中也會與tau蛋白共沈積在一起，與之前的細胞模式實驗結果相同。我們的研究結果將會提供一個治療包括阿茲海默症以及其他tauopathy的契機，透過HDAC inhibitors 藥物的投與，促進基因轉錄以治療tau所造成的TBP功能缺失。
Previous studies found that the TATA box-binding protein (TBP) is sequestered by tau-mediated neurofibrillary tangles (NFTs) in the brain of postmortem Alzheimer’s disease (AD) patients, suggesting that down-regulation of TBP may involve in the pathogenesis of tauopathy. Since TBP controls virtually the transcription of all genes, to further demonstrate that transcription dysfunction is a causative factor of tauopathy, we have used an established tauopathy fly model expressing normal human tau. We found that treating HDAC inhibitors, including SAHA, can rescue bristle loss phenotype induced by the ectopic tau in the notum of the transgenic flies. Our findings suggested that transcription dysfunction might contribute to tau-mediated neurodegeneration. In this study, we found that TBP is co-localized with NFTs in HEK-293T cells. We also showed that the transactivation function of TBP is affected by fibrogenic tau species. To confirm our finding in animal model, we generated novel Drosophila tauopathy models by expressing fibrogenic tau species. We have found that the fly models exhibit shortened lifespan. We also found that it would form insoluble fibrogenic protein in transgenic flies. To address if TBP is also mis-localized with NFTs in our transgenic flies, we examined transgenic fly’s brain and discovered that TBP is co-localized with tau as seen in the cultured cells. In summary, my study has unraveled a novel pathogenic mechanism of tauopathy, and shown a possible cure for tauopathies including Alzheimer’s disease by treating HDAC inhibitors.
Previous studies found that the TATA box-binding protein (TBP) is sequestered by tau-mediated neurofibrillary tangles (NFTs) in the brain of postmortem Alzheimer’s disease (AD) patients, suggesting that down-regulation of TBP may involve in the pathogenesis of tauopathy. Since TBP controls virtually the transcription of all genes, to further demonstrate that transcription dysfunction is a causative factor of tauopathy, we have used an established tauopathy fly model expressing normal human tau. We found that treating HDAC inhibitors, including SAHA, can rescue bristle loss phenotype induced by the ectopic tau in the notum of the transgenic flies. Our findings suggested that transcription dysfunction might contribute to tau-mediated neurodegeneration. In this study, we found that TBP is co-localized with NFTs in HEK-293T cells. We also showed that the transactivation function of TBP is affected by fibrogenic tau species. To confirm our finding in animal model, we generated novel Drosophila tauopathy models by expressing fibrogenic tau species. We have found that the fly models exhibit shortened lifespan. We also found that it would form insoluble fibrogenic protein in transgenic flies. To address if TBP is also mis-localized with NFTs in our transgenic flies, we examined transgenic fly’s brain and discovered that TBP is co-localized with tau as seen in the cultured cells. In summary, my study has unraveled a novel pathogenic mechanism of tauopathy, and shown a possible cure for tauopathies including Alzheimer’s disease by treating HDAC inhibitors.
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阿茲海默症, TBP, Tauopathy, TBP