ROLE OF TFEB IN TAUOPATHY

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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.