降低組蛋白去乙醯酶活性減緩果蠅模式之Tau蛋白神經毒性之研究

Abstract

Tau是一個被大量表現在中樞神經系統之中的蛋白，其功能為穩固神經細胞之中微管的結構，並維持神經系統的完整性。Tau蛋白在過度磷酸化及不正常聚集會造成許多退化性神經疾病通稱為”tauopathies”。這些疾病包括了阿茲海默氏症以及額顳葉失智症。由於研究顯示基因轉錄失調為tauopathies 的致病機轉之一，且抑制組蛋白去乙醯酶可改善上述病徵。因此本研究的目的在於利用果蠅模式，藉由組蛋白去乙醯酶抑制劑及核酸干擾檢驗上述推論。我們先前研究發現在果蠅過量表現人類的Tau蛋白會造成背甲上的剛毛缺少，利用此一模式以核酸干擾的方式，發現降低果蠅的組蛋白去乙醯酶的表現能有效的抑制因Tau蛋白表現所造成剛毛缺失的現象，同樣地，利用一些新穎的組蛋白去乙醯酶抑制劑也可以達到改善剛毛生長的情況，進一步我們發現核酸干擾及抑制劑的處理可增加組蛋白H3的乙醯化。而核酸干擾及組蛋白去乙醯酶抑制劑的處理會降低Tau及Tau磷酸化的表現以及提升Tau的溶解度。然而核酸干擾及部分組蛋白去乙醯酶抑制劑可增加Tau果蠅模式的壽命。綜合上述發現，我們認為降低Tau蛋白的表現量和磷酸化及增加組蛋白H3的乙醯化，可能對病徵有改善的作用。Tau is a neuronal enriched protein whose function is to stabilize the structure of microtubules, and maintain the integrity of neuron. However, it was found that hyperphosophorylation and aberrant accumulation of Tau in the neurons can cause a group of neurodegenerations, including Alzheimer’s disease and frontotemporal dementia, which are collectively called tauopathies. Since it was reported that transcriptional dysfunction is one of the main pathomechanisms of tauopathies and inhibition of histone deactylase (HDAC) can enhance transcription and ameliorate the neuronal impairments, we would like to address the question using Drosophila as a model system. The aims of my study is to inactivate HDAC by either RNA interference (RNAi) or HDAC inhibitors (HDACIs) to test if down-regulation of HDAC is beneficialin reducing Tau toxicity in flies. We found that the notal bristle was increased in Tau-expressing flies when HDACs were knocked down by RNAi. Similarly, some novel HDAC inhibitors can exhibits same beneficial effects. We further discovered that the expression of acetylated histone H3 was increased when treated with RNAi or a dietary HDACI, Sulforaphane (SFN). The expression and phosphorylation of Tau were decrease in both treatment, and increase the solubility of Tau. Additionally, knocking down most HDAC or SFN treatment can extend the lifespan of tau expressing flies. In sum, my studies suggest that phosophorylated Tau might be the main causes of tauopathies. On the contrary, inhibition of HDAC might be beneficial to tauopathies.