# ROLE OF TFEB IN TAUOPATHY

> **NIH NIH RF1** · BAYLOR COLLEGE OF MEDICINE · 2021 · $1,511,862

## Abstract

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.

## Key facts

- **NIH application ID:** 10208141
- **Project number:** 2RF1NS093652-06
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hui Zheng
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,511,862
- **Award type:** 2
- **Project period:** 2015-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208141

## Citation

> US National Institutes of Health, RePORTER application 10208141, ROLE OF TFEB IN TAUOPATHY (2RF1NS093652-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10208141. Licensed CC0.

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