A TFEB and V-ATPase-mediated lysosomal stress sensing pathway in tauopathy

摘要 Tauopathies由一组疾病组成，包括额颞叶痴呆和最常见的形式 阿尔茨海默病，其特征在于细胞内神经元缠结（NFT）的积累 由过度磷酸化的Tau蛋白聚集体和广泛的神经变性组成。积累 有证据表明，神经退行性疾病中的自噬-溶酶体途径受损， 老年痴呆症转录因子EB（TFEB）被发现是细胞凋亡的主要调节因子。 通过自噬和溶酶体靶基因的协调表达清除。我们发现 TFEB在改善Tau转基因小鼠中的Tau/NFT病理和行为缺陷方面是高度有效的 同时对野生型小鼠没有表现出不利影响，支持TFEB可能作为潜在的 治疗靶点该项目的总体目标是研究Tau诱导的TFEB溶酶体- 核信号通路调节溶酶体稳态和细胞清除在生理和 本发明的目的是提供一种用于治疗tau蛋白病病症的方法，并鉴定增强该途径以增强细胞清除的策略。 具体来说，通过蛋白质组学分析tau蛋白病小鼠模型，我们将确定如何Tau病理 诱导独特的TFEB翻译后修饰和核信号传导。通过利用强大的 溶酶体纯化和分析系统由计划项目赠款研究人员提供，我们将 测试Tau病理学如何改变溶酶体蛋白质组，代谢组和pH值，后者对于 溶酶体的功能和关键控制的液泡ATP酶（V-ATP酶）。因此，我们将测试 特异性TFEB/V-ATP酶信号转导在Tau发病机制和下游神经胶质细胞和免疫应答中的作用。这 该项目是该计划项目赠款的一个组成部分，旨在了解溶酶体的功能 是通过溶酶体到细胞核的信号通路调节的，这些通路在衰老中是如何改变的， 阿尔茨海默病，以及如何利用这些调节途径来促进大脑健康，对抗年龄- 相关的功能下降，并延缓神经退行性疾病。该项目与 计划项目赠款的合作努力，将创造一流的老化和Tauopathy相关 小鼠皮层和海马的溶酶体蛋白质组和代谢组的溶酶体图谱（ATLas） 这将广泛提供给研究界。

Abstract Tauopathies consist of a group of diseases, including frontotemporal dementias and the most common form Alzheimer’s disease, and are characterized by the accumulation of intracellular neurofibrillary tangles (NFTs) composed of aggregates of hyperphosphorylated Tau protein and extensive neurodegeneration. Accumulating evidence has implicated impaired autophagy-lysosome pathway in neurodegenerative diseases including Alzheimer’s disease. The Transcription Factor EB (TFEB) was discovered as a master regulator of cellular clearance through coordinated expression of autophagy and lysosomal target genes. We have found that TFEB is highly efficacious in ameliorating Tau/NFT pathology and behavioral deficits in Tau transgenic mice while exhibiting no adverse effect on wild-type mice, supporting the premise that TFEB may serve as potential therapeutic target. The overarching goal of this project is to investigate a Tau-induced TFEB lysosome-to- nucleus signaling pathway regulating lysosomal homeostasis and cellular clearance in physiological and tauopathy conditions and to identify strategies to augment this pathway for enhanced cellular clearance. Specifically, through proteomics analysis of tauopathy mouse models, we will identify how Tau pathology induces unique TFEB post-translational modifications and nuclear signaling. By leveraging the powerful lysosomal purification and profiling system made available by the Program Project Grant investigators, we will test how Tau pathology alters the lysosomal proteome, metabolome, and pH, the latter is essential for lysosomal function and critically controlled by the vacuolar ATPase (V-ATPase). Accordingly, we will test the specific TFEB/V-ATPase signaling in Tau pathogenesis and downstream glia and immune response. This project is an integral component of the Program Project Grant aimed at understanding how lysosomal function is regulated through lysosome-to-nucleus signaling pathways, how these pathways are changed in aging and Alzheimer’s disease, and how to harness these regulatory pathways to promote brain health, combat age- associated functional decline, and delay neurodegenerative diseases. This project, together with the collaborative efforts of the Program Project Grant, will create a first-in-class Aging- and Tauopathy-associated Lysosomal atlas (ATLas) of the lysosomal proteome and metabolome for mouse cortex and hippocampus which will be made broadly available to the research community.