CELL-CELL TRANSFER AND PROPAGATION OF TAU AGGREGATES

描述（由申请人提供）：细胞-细胞转移和tau聚集体的繁殖。牛头病是毁灭性的神经退行性疾病。所有这些疾病在病理上都与微管相关蛋白tau的错误折叠和聚集有关，包括阿尔茨海默病和额颞叶痴呆等常见疾病。野生型tau蛋白和与显性遗传疾病相关的突变形式都有错误折叠和聚集的倾向。在几乎所有的病例中，疾病都是从大脑的一个区域开始的，然后扩散到其他区域，并且有新的证据表明，这可能是基于细胞之间蛋白质聚集体的运动。该项目旨在了解控制tau聚集体从细胞中摄取和释放的细胞机制，以及进入细胞的tau聚集体如何设法破坏内源性，正常折叠的蛋白质。这些问题的答案将立即为治疗策略提供新的机会。本研究的目标如下：(1)确定tau蛋白摄取的分子机制。我们将使用我们已经开发的基于细胞的分析来研究tau聚集体的摄取，并评估这种现象背后的分子机制。我们将使用小鼠模型来测试我们在细胞模型中实验得出的通路预测。(2)确定tau聚集体降解和释放的机制。我们认为，与蛋白质降解相关的细胞通路可能在处理tau蛋白聚集体中发挥作用，也可能参与允许这些聚集体在细胞之间转移。我们将使用细胞间聚集转移的细胞模型来测试这些想法。(3)确定tau聚集传播机制。目前尚不清楚tau蛋白聚集如何从一个细胞移动到另一个细胞可能导致受体细胞中蛋白质的错误折叠，以及这种移动是否可以发生在突触之间，正如新的临床研究所表明的那样。我们将测试tau蛋白是否通过模板化的构象改变在细胞内部聚集“腐败”蛋白质，即正常折叠的蛋白质直接接触聚集形式。我们还将使用一种新的小鼠模型测试聚集体是否可以在突触之间移动。

DESCRIPTION (provided by applicant): Cell-cell transfer and propagation of tau aggregates. Tauopathies are devastating neurodegenerative diseases. All are linked pathologically to misfolding and aggregation of the microtubule-associated protein tau, and include common disorders such as Alzheimer disease and frontotemporal dementia. Both wild-type tau protein and mutant forms associated with dominantly inherited diseases have the propensity to misfold and aggregate. In virtually all cases, disease begins in one brain region before spreading to involve other regions, and there is emerging evidence that this could be based on movement of protein aggregates between cells. This project seeks to understand the cellular mechanisms that govern tau aggregate uptake and release from cells, and how a tau aggregate taken into a cell manages to corrupt the endogenous, normally folded protein. The answers to these questions will provide immediate new opportunities for therapeutic strategies. The goals of this work are as follows: (1) Determine molecular mechanisms of tau uptake. We will use cell-based assays we have developed to study tau aggregate uptake, and to evaluate the molecular mechanisms that underlie this phenomenon. We will use mouse models to test predictions about pathways derived from our experiments in cell models. (2) Determine mechanisms of tau aggregate degradation and release. We believe that cellular pathways linked to protein degradation may play a role in processing tau protein aggregates, and might also be involved in allowing these aggregates to transfer between cells. We will test these ideas using a cellular model of aggregate transfer between cells. (3) Determine mechanisms of tau aggregate propagation. It is unclear how tau protein aggregates that move from one cell to another might lead to misfolding of protein in the recipient cell, and whether this movement can occur across synapses, as is suggested by new clinical studies. We will test whether tau protein aggregates "corrupt" protein on the cell interior through templated conformation change, whereby normally folded protein directly contacts aggregated forms. We will additionally test whether aggregates can move across synapses using a novel mouse model. PUBLIC HEALTH RELEVANCE: Tauopathies afflict millions of Americans, and hundreds of millions of individuals worldwide. As our population ages, the incidence of these diseases will rise acutely. There is no cure, and we lack sufficient mechanistic understanding of pathogenesis to design well-targeted therapies. This research will help solve these problems, as it is focused on understanding the cellular mechanisms that influence pathogenesis.