Dataset Information

TFEB-vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy.

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) essential for lysosome acidification. Single nucleus RNA-sequencing (snRNA-seq) of wild-type and PS19 (Tau) transgenic mice 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. We show that the 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 was locked in a homeostatic state. Our studies demonstrate a physiological function of TFEB-v-ATPase signaling in maintaining lysosomal homoeostasis and a critical role of the lysosome in mounting a microglia and immune response in tauopathy and Alzheimer's disease.

SUBMITTER: Wang B

PROVIDER: S-EPMC9934527 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TFEB-vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy.

Wang Baiping B Martini-Stoica Heidi H Qi Chuangye C Lu Tzu-Chiao TC Wang Shuo S Xiong Wen W Qi Yanyan Y Xu Yin Y Sardiello Marco M Li Hongjie H Zheng Hui H

bioRxiv : the preprint server for biology 20230206

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) essential for lysosome acidification. Single nucleus RNA-sequencing (snRNA-seq) of wild-type and PS19 (Tau) transgenic mice identified three unique microglia subclusters in Tau mice that were associated with heightened lysosome and immune pathway genes. To explore the lysosome-immune relatio ...[more]

PMID: 36798205

Similar Datasets

Project description:Cognitive impairment caused by systemic chemotherapy is a critical question that perplexes the effective implementation of clinical treatment, but related molecular events are poorly understood. Herein, we show that bortezomib exposure leads to microglia activation and cognitive impairment, this occurs along with decreased nuclear translocation of TFEB (transcription factor EB), which is linked to macroautophagy/autophagy disorder, STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL23A (interleukin 23 subunit alpha) expression. Pharmacological enhancement of TFEB nuclear translocation by digoxin restores lysosomal function and reduces STAT3-dependent endothelial IL23A secretion. As a consequence, we found that brain endothelial-specific ablation of Il23a ameliorated both microglia activation and cognitive dysfunction. Thus, the endothelial TFEB-STAT3-IL23A axis in the brain represents a critical cellular event for initiating bortezomib-mediated aberrant microglial activation and synapse engulfment. Our results suggest the reversal of TFEB nuclear translocation may provide a novel therapeutic approach to prevent symptoms of cognitive dysfunction during clinical use of bortezomib.Abbreviations: AAV: adeno-associated virus; BBB: blood-brain barrier; BTZ: bortezomib; DG: digoxin; DGs: dentate gyrus; DLG4/PSD95: discs large MAGUK scaffold protein 4; HBMECs: human brain microvascular endothelial cells; HP: hippocampus; IL23A: interleukin 23 subunit alpha; MBVECs: mouse brain vascular endothelial cells; mPFC: medial prefrontal cortex; NORT: novel object recognition test; OLT: object location test; PLX5622: 6-fluoro-N-([5-fluoro-2-methoxypyridin-3-yl]methyl)-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3- yl)methyl; PPP3/calcineurin: protein phosphatase 3; SBEs: STAT3 binding elements; shRNA: small hairpin RNA; SLC17A7/VGLUT1: solute carrier family 17 member 7; SLC32A1/VGAT: solute carrier family 32 member 1; STAT3: signal transducer and activator of transcription 3, TFEB: transcription factor EB; Ub: ubiquitin.

Project description:Manganese (Mn) is a neurotoxin that has been etiologically linked to the development of neurodegenerative diseases in the case of overexposure. It is widely accepted that overexposure to Mn leads to manganism, which has clinical symptoms similar to Parkinson's disease (PD), and is referred to as parkinsonism. Astrocytes have been reported to scavenge and degrade extracellular α-synuclein (α-Syn) in the brain. However, the mechanisms of Mn-induced neurotoxicity associated with PD remain unclear. Serpina3n is highly expressed in astrocytes and has been implicated in several neuropathologies. The role Serpina3n plays in Mn neurotoxicity and PD pathogenesis is still unknown. Here, we used wild-type and Serpina3n knockout (KO) C57BL/6 J mice with i.p. injection of 32.5 mg/kg MnCl2 once a day for 6 weeks to elucidate the role of Serpina3n in Mn-caused neurotoxicity regarding parkinsonism pathogenesis. We performed behavioral tests (open field, suspension and pole-climbing tests) to observe Mn-induced motor changes, immunohistochemistry to detect Mn-induced midbrain changes, and Western blot to detect Mn-induced changes of protein expression. It was found that Serpina3n KO markedly alleviated Mn neurotoxicity in mice by attenuating midbrain dopaminergic neuron damage and ameliorating motor deficits. Furthermore, using immunofluorescence colocalization analysis, Western blot and quantitative real-time PCR on Mn-treated C8-D1A cells, we found that Serpina3n KO significantly improved astrocytic α-Syn clearance by suppressing Mn-induced lysosomal dysfunction. Reduced transcription factor EB (TFEB)-v/p-ATPase signaling is responsible for the impairment of the lysosomal acidic environment. These novel findings highlight Serpina3n as a detrimental factor in Mn neurotoxicity associated with parkinsonism, capture the novel role of Serpina3n in regulating lysosomal function, and provide a potential target for antagonizing Mn neurotoxicity and curing parkinsonism in humans.

Dataset Information

TFEB-vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy.

Publications

TFEB-vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets