Hyperphosphorylated tau and the molecular mechanisms of tauopathy

tau蛋白过度磷酸化与tau蛋白病的分子机制 Tau蛋白病是神经退行性疾病，在中枢神经系统中共有Tau蛋白的共同病理学。 神经系统最突出的tau蛋白病是阿尔茨海默病（AD），影响近600万人 美国人和全世界3000多万人。动物和细胞研究表明， 寡聚体过度磷酸化的tau蛋白对细胞有毒，并且可以朊病毒样方式在脑中传递。然而，在这方面， 过度磷酸化如何将tau蛋白转化为细胞毒性物质，以及过度磷酸化的tau蛋白如何发挥其 细胞毒性尚不清楚。因此，有效的tau蛋白病治疗剂的开发仍然是一个艰巨的挑战。 挑战. 该R 01项目旨在使用重组过度磷酸化tau（p-tau）作为模型来检查 tau蛋白病的分子机制具体而言，我们希望回答两个主要问题： 过度磷酸化的tau蛋白会损伤或杀死细胞吗？是什么让tau蛋白成为一种细胞毒性物质？我们将执行 蛋白质组学研究，以确定p-tau的目标，这可能导致实现新的可药用目标， 治疗学设计我们还将精确定位tau蛋白的磷酸化残基， 修饰，驱动致病物种的发生和传播。最后，我们发现， 细胞毒性p-tau原纤维的形成受到ApoE脂蛋白和选择性β-内酰胺酶的调节。 胆固醇的代谢物。将进行生化和细胞研究以解开分子细节， 这将有助于我们了解不同的ApoE等位基因如何促进阿尔茨海默氏症的发展 疾病，以及胆固醇代谢是如何机械地与这种毁灭性的疾病。

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.