Project 3: Autophagy dysfunction and neuronal activity in FTD

项目3：FTD Ana Maria Cuervo中的自噬功能障碍和神经元活性 总结 该提案调查了tau蛋白的致病形式和自噬的选择性形式之间的相互作用， 额颞叶痴呆（FTD）我们将协调这一项目的活动与 项目1和项目2来检验我们的工作假设，即自噬途径中的tau介导的毒性 是在FTD影响的神经元中观察到的tau蛋白稳态改变和功能改变的基础。 项目3将在iPSC衍生的神经元中使用尖端蛋白质组学（MS Core）和遗传学（CRISPR Core）， 研究：1）致病性胞内和胞外tau蛋白在三种不同形式的选择性 自噬; 2）阻断这些形式的自噬中的每一种对神经元活性和tau蛋白的影响 摄取。项目3还将利用来自对照组和FTD-tau患者的死后冷冻人脑组织 （人类核心），以确定3）与自噬区室相关的tau性质的变化， 控制和病人的大脑。在CRISPR核心的帮助下，我们将调节不同的tau蛋白水平， 相互作用的蛋白质，并解决这种干预对自噬和神经元活性的影响。 将本项目产生的数据（数据核心）与中心其他两个项目产生的数据进行整合， 使我们能够阐明tau蛋白对自噬系统的毒性对神经元活性失衡的贡献 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.