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

> **NIH NIH P01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $513,147

## Abstract

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.

## Key facts

- **NIH application ID:** 10413975
- **Project number:** 5P01AG066606-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hui Zheng
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $513,147
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413975

## Citation

> US National Institutes of Health, RePORTER application 10413975, A TFEB and V-ATPase-mediated lysosomal stress sensing pathway in tauopathy (5P01AG066606-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10413975. Licensed CC0.

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