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

摘要 变态反应由一组疾病组成，包括额颞部痴呆和最常见的形式 阿尔茨海默病，以细胞内神经原纤维缠结(NFTs)堆积为特征 由过度磷酸化的Tau蛋白和广泛的神经变性的聚集体组成。积累 有证据表明自噬-溶酶体途径受损与神经退行性疾病有关，包括 阿尔茨海默氏症。转录因子EB(TFEB)被发现是细胞内的主要调节因子 通过自噬和溶酶体靶基因的协调表达清除。我们发现， TFEB对Tau转基因小鼠Tau/NFT病理和行为障碍的改善作用 同时对野生型小鼠没有不良影响，支持TFEB可能作为潜在的 治疗靶点。这个项目的主要目标是研究Tau诱导的TFEB溶酶体到- 核信号通路调节溶酶体稳态和细胞清除 并确定增强这一途径以增强细胞清除的策略。 具体地说，通过对Tau病小鼠模型的蛋白质组学分析，我们将确定Tau病理是如何 诱导独特的TFEB翻译后修饰和核信号转导。通过利用强大的 由项目资助研究人员提供的溶酶体纯化和图谱系统，我们将 测试Tau病理如何改变溶酶体蛋白质组、代谢组和pH，后者对 溶酶体的功能和关键控制的空泡ATPase(V-ATPase)。因此，我们将测试 特异性TFEB/V-ATPase信号在Tau发病机制及下游胶质细胞和免疫应答中的作用这 项目是项目资助计划的一个组成部分，旨在了解溶酶体如何发挥作用 是通过溶酶体到核的信号通路来调节的，这些通路在衰老和 阿尔茨海默氏症，以及如何利用这些调控途径来促进大脑健康，对抗年龄- 相关功能衰退，延缓神经退行性疾病。这个项目，连同 在计划项目赠款的共同努力下，将创建一流的与衰老和脊椎病相关的 小鼠大脑皮层和海马区溶酶体蛋白质组和代谢组图谱 它将向研究界广泛提供。

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.