TFEB-vacuolar ATPase Signaling Regulates Lysosomal Function and Microglial Activation in Tauopathy

Overview

Journal Nat Neurosci

Date 2023 Nov 21

PMID 37985800

Authors

Baiping Wang

Heidi Martini-Stoica

Chuangye Qi

Tzu-Chiao Lu

Shuo Wang

Wen Xiong

Yanyan Qi

Yin Xu

Marco Sardiello

Hongjie Li

Hui Zheng

Affiliations

Soon will be listed here.

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.

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