ROLE OF TFEB 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(AD)，以细胞内神经原纤维缠结堆积为特征 (NFTS)由过度磷酸化的Tau蛋白和广泛的神经变性的聚集体组成。 越来越多的证据表明神经退行性疾病中自噬-溶酶体途径受损 包括公元。转录因子EB(TFEB)被发现是细胞内的主要调节因子 通过细胞质到核转位发挥作用的清除，在那里它介导协调表达 自噬和溶酶体靶基因。我们在当前赠款周期中的研究揭示了多细胞的作用 TFEB在解决Tau/NFT病理中的作用。具体地说，神经元TFEB在改善脑功能方面非常有效 Tau/NFT病理与认知功能障碍和神经退行性变的挽救 防止Tau在Tau病小鼠模型中的病理扩散。值得注意的是，我们发现TFEB的目标是 只有异常的Tau物种，而保持正常的Tau完好无损，这表明病理性Tau是 TFEB的上游激活剂。支持这一前提的是，对人类阿尔茨海默病大脑和 Tau转基因小鼠都表现出TFEB及其溶酶体靶标的显著上调。 V-ATPase的多个亚基对溶酶体的酸化和功能至关重要，从而记录了 保守的TFEB/V-ATPase介导的溶酶体对疾病病理的反应。此外，我们发现了一个小的 促进mTOR非依赖性TFEB核定位的分子溶酶体脂质信号分子 举止。本项目的主要目标是研究Tau诱导的TFEB信号通路的调控 生理性和自律性条件下溶酶体的动态平衡，并确定针对这一点的策略 增强Tau清除的途径。具体地说，通过无偏见的蛋白质组学分析，我们将确定 Tau病理如何诱导独特的TFEB翻译后修饰和核信号转导，我们将测试 它们对牛磺酸降解的影响。我们将研究一种新的核出口机制，以调解mTOR- 独立的TFEB活动。基于我们令人兴奋的发现TFEB/V-ATPase介导的溶酶体信号 通路在调节星形胶质细胞和小胶质细胞对神经元性Tau病理的反应中起重要作用 将询问这种溶酶体免疫系统的分子机制和功能后果 两性关系。总体而言，我们将深入了解溶酶体功能是如何通过 溶酶体到核的信号通路，这些通路在阿尔茨海默病和变态反应条件下是如何改变的， 以及如何利用这些调控途径进行治疗干预。

Abstract Tauopathies consist of a group of diseases, including frontotemporal dementias and the most common form Alzheimer’s disease (AD), 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-lysosomal pathway in neurodegenerative diseases including AD. The Transcription Factor EB (TFEB) was discovered as a master regulator of intracellular clearance that functions by cytoplasm-to-nucleus translocation, where it mediates coordinated expression of autophagy and lysosomal target genes. Our studies in the current grant cycle revealed a multi-cellular role of TFEB in addressing the Tau/NFT pathology. Specifically neuronal TFEB is highly efficacious in ameliorating Tau/NFT pathology and rescue of cognitive impairment and neurodegeneration, whereas astroglial TFEB prevents Tau pathological spreading in tauopathy mouse models. Significantly, we found that TFEB targets only the aberrant Tau species while leaving the normal Tau intact, indicating that pathological Tau serves as an upstream activator of TFEB. Supporting this premise, RNA-sequencing analysis of human AD brains and Tau transgenic mice both revealed significant upregulation of TFEB and its lysosomal targets, in particular multiple subunits of the V-ATPase critical for lysosomal acidification and function, thus documenting a conserved TFEB/V-ATPase-mediated lysosomal response to disease pathology. Further, we identified a small molecule lysosomal lipid signaling molecule that promotes TFEB nuclear localization in an mTOR-independent manner. The overarching goal of this project is to investigate Tau-induced TFEB signaling pathway regulating lysosomal homeostasis in physiological and tauopathy conditions and to identify strategies that target this pathway for enhanced Tau clearance. Specifically, through unbiased proteomics analysis, we will determine how Tau pathology induces unique TFEB post-translational modifications and nuclear signaling and we will test their effect on Tau degradation. We will examine a novel nuclear export mechanism in mediating mTOR- independent TFEB activity. Build on our exciting finding that TFEB/V-ATPase-mediated lysosomal signaling pathway plays an essential role in regulating astrocyte and microglia response to neuronal Tau pathology, we will interrogate the molecular mechanisms and functional consequences of this lysosome-immune system relationship. Overall we will achieve deep understanding on how lysosomal function is regulated through lysosome-to-nucleus signaling pathways, how these pathways are changed in AD and tauopathy conditions, and how to harness these regulatory pathways for therapeutic intervention.