Project 3: Autophagy dysfunction and neuronal activity in FTD

项目3：FTD Ana Maria Cuervo自噬功能障碍和神经元活动 摘要 这项建议调查了tau的致病形式和选择性自噬形式之间的相互作用。 额颞性痴呆(FTD)的背景。我们将协调这个项目的活动与 项目1和项目2来验证我们的工作假设，即tau在自噬途径中介导的毒性 这是在FTD影响的神经元中观察到的tau蛋白稳定和功能改变的基础。 项目3将在IPSC来源的神经元中使用尖端蛋白质组学(MS Core)和遗传学(CRISPR Core)来 研究：1)致病细胞内外tau对三种不同形式的选择素活性的影响 自噬；2)阻断每种形式的自噬对神经元活性和tau的影响 领悟。项目3还将利用对照组和FTD-tau患者死后冰冻的人脑组织 (人体核心)确定3)与自噬隔间有关的tau的性质变化 控制和耐心的大脑。在CRISPR核心的协助下，我们将调节不同tau的水平- 并解决这种干预对自噬和神经元活动的影响。 将该项目生成的数据(数据核心)与中心的其他两个项目生成的数据进行集成 允许我们阐明tau毒性对自噬系统在神经元活动失衡中的作用。 在FTD中观察到。

Project 3: Autophagy dysfunction and neuronal activity in FTD Ana Maria Cuervo SUMMARY This proposal investigates the interplay between pathogenic forms of tau and selective forms of autophagy in the context of frontotemporal dementia (FTD). We will coordinate the activities of this project with those of Project 1 and Project 2 to test our working hypothesis that tau-mediated toxicity in the autophagic pathways underlie the basis for the altered tau proteostasis and functional alterations observed in FTD-affected neurons. Project 3 will use cutting edge proteomics (MS Core) and genetics (CRISPR Core) in iPSC-derived neurons to investigate: 1) effect of pathogenic intra- and extracellular tau in the activity of three different forms of selective autophagy; 2) consequences of blockage of each of these forms of autophagy on neuronal activity and tau uptake. Project 3 will also utilize postmortem frozen human brain tissue from controls and FTD-tau patients (Human Core) to identify 3) changes in the properties of tau associated with autophagic compartments in control and patient brains. Assisted by the CRISPR Core, we will modulate levels of differentially tau- interacting proteins and address the effect of this intervention on autophagy and neuronal activity. Integration of data (Data Core) generated by this project with that from the other two projects in the Center will allow us to elucidate the contribution of tau toxicity on the autophagic system to the neuronal activity imbalance observed in FTD.