Language
English
Publication Date
1-1-2024
Journal
Nature Neuroscience
DOI
10.1038/s41593-023-01494-2
PMID
37985800
PMCID
PMC12203451
PubMedCentral® Posted Date
6-27-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Transcription factor EB (TFEB) mediates gene expression through binding to the coordinated lysosome expression and regulation (CLEAR) sequence. TFEB targets include subunits of the vacuolar ATPase (v-ATPase), which are essential for lysosome acidification. Single-nucleus RNA sequencing of wild-type and PS19 (Tau) transgenic mice expressing the P301S mutant tau identified three unique microglia subclusters in Tau mice that were associated with heightened lysosome and immune pathway genes. To explore the lysosome-immune relationship, we specifically disrupted the TFEB-v-ATPase signaling by creating a knock-in mouse line in which the CLEAR sequence of one of the v-ATPase subunits, Atp6v1h, was mutated. CLEAR mutant exhibited a muted response to TFEB, resulting in impaired lysosomal acidification and activity. Crossing the CLEAR mutant with Tau mice led to higher tau pathology but diminished microglia response. These microglia were enriched in a subcluster low in mTOR and HIF-1 pathways and were locked in a homeostatic state. Our studies demonstrate a physiological function of TFEB-v-ATPase signaling in maintaining lysosomal homeostasis and a critical role of the lysosome in mounting a microglia and immune response in tauopathy and Alzheimer's disease.
Keywords
Animals, Mice, Autophagy, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Lysosomes, Mice, Transgenic, Microglia, Signal Transduction, Tauopathies, Vacuolar Proton-Translocating ATPases
Published Open-Access
yes
Recommended Citation
Wang, Baiping; Martini-Stoica, Heidi; Qi, Chuangye; et al., "TFEB-Vacuolar ATPase Signaling Regulates Lysosomal Function and Microglial Activation in Tauopathy" (2024). Huffington Center on Aging Staff Publications. 49.
https://digitalcommons.library.tmc.edu/aging_research/49