Hyperphosphorylated tau and the molecular mechanisms of tauopathy

过度磷酸化tau与tau病的分子机制 Tau病是一种神经退行性疾病，与中枢tau蛋白具有共同的病理特征。 神经系统。最突出的肌萎缩侧索硬化症是阿尔茨海默病(AD)，影响了近600万人 美国人和全球3000多万人。动物和细胞研究表明，可溶性的， 寡聚体过度磷酸化的tau对细胞有毒，并可以在大脑中以类似普里恩的方式传播。然而， 过度磷酸化如何将tau转化为细胞毒性物种，以及过度磷酸化tau如何发挥其 细胞毒性尚不清楚。因此，开发有效的相互作用疗法仍然是一项艰巨的任务。 挑战。 本R01项目旨在使用重组过磷酸化tau(p-tau)作为模型来检验 紧张症背后的分子机制。具体来说，我们希望回答两个主要问题：如何 过度磷酸化的tau会损伤或杀死细胞吗？是什么让tau成为一种细胞毒性物种？我们将表演 蛋白质组学研究确定p-tau的靶点，可能导致未来实现新的可用药靶点 治疗设计。我们还将确定tau蛋白的可磷酸化残基， 修饰，驱动一种致病物种的发生和传播。最后，我们发现， 细胞毒性p-tau纤维的形成受ApoE脂蛋白和选择性 胆固醇的代谢物。生物化学和细胞研究将被用来揭开分子细节， 这将有助于我们理解不同的ApoE等位基因是如何在阿尔茨海默氏症的发展中起作用的 疾病，以及胆固醇代谢如何与这种毁灭性的疾病机械地联系在一起。

Hyperphosphorylated tau and the molecular mechanisms of tauopathy Tauopathies are neurodegenerative disorders sharing the common pathology of the tau protein in the central nervous system. The most prominent tauopathy is Alzheimer’s disease (AD) that affects nearly 6 million Americans and more than 30 million people worldwide. Animal and cell studies demonstrated that soluble, oligomeric hyperphosphorylated tau is toxic to cells, and can transmit in a prion-like fashion in the brain. However, how hyperphosphorylation converts tau into a cytotoxic species, and how hyperphosphorylated tau exerts its cytotoxicity are unclear. As such, development of efficacious tauopathy therapeutics remains a formidable challenge. This R01 project aims to use a recombinant hyperphosphorylated tau (p-tau) as the model to examine the molecular mechanisms underlying tauopathies. Specifically, we wish to answer two major questions: how does hyperphosphorylated tau damage or kill cells? And what makes tau a cytotoxic species? We will perform proteomics studies to identify targets of p-tau that may lead to the realization of novel druggable targets for future therapeutics design. We will also pinpoint the phosphorylatable residues of the tau protein that, upon modification, drive the genesis and transmission of a pathogenic species. Finally, we have found that the formation of cytotoxic p-tau fibrils is subjected to the regulation of the ApoE lipoprotein and of selective metabolites of cholesterol. Biochemical and cell studies are to be performed to unravel the molecular details, which will facilitate our understanding of how different ApoE alleles contribute to the development of Alzheimer’s disease, as well as how cholesterol metabolism is mechanistically linked to this devastating disease.