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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), 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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Fig. 1: Elevated TFEB and lysosomal pathway in PS19 (Tau) mice and by insoluble tau.
Fig. 2: snRNA-seq revealed lysosome and immune pathway upregulation in microglia of Tau mice.
Fig. 3: Shift of microglia subclusters in Tau mice.
Fig. 4: Generation of an in vivo model of lysosomal dysfunction through CLEAR mutagenesis.
Fig. 5: Increased phospho-tau and decreased gliosis in Tau mice crossed to CL background.
Fig. 6: Disruption of TFEB–v-ATPase lysosomal signaling leads to impaired microglia morphology and activation.
Fig. 7: snRNA-seq analysis identified a distinct homeostatic microglia subcluster regulated by TFEB–v-ATPase.
Fig. 8: Disruption of TFEB–v-ATPase regulation leads to compromised lysosomal and inflammatory changes and reduced mTOR and HIF-1 signaling in tauopathy.

Data availability

Bulk hippocampus RNA-seq and snRNA-seq data generated in this study have been deposited in the GEO with accession number: GSE218728. Public TFEB ChIP-seq in THP1 cell line was downloaded from NCBI with the accession number GSE217608. Any additional information on sequencing data reported in this paper is available upon request. Source data are provided with this paper.

Code availability

The scripts for snRNA-seq and bulk RNA-seq analysis were deposited at https://github.com/qicy2014/snRNA_bulkRNAseq.git.

References

  1. Ballabio, A. & Bonifacino, J. S. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 21, 101–118 (2020).

    CAS  PubMed  Google Scholar 

  2. Colacurcio, D. J. & Nixon, R. A. Disorders of lysosomal acidification—the emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Res. Rev. 32, 75–88 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Settembre, C., Fraldi, A., Medina, D. L. & Ballabio, A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14, 283–296 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).

    CAS  PubMed  Google Scholar 

  5. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Palmieri, M. et al. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum. Mol. Genet. 20, 3852–3866 (2011).

    CAS  PubMed  Google Scholar 

  7. Xiao, Q. et al. Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis. J. Neurosci. 34, 9607–9620 (2014).

    PubMed  PubMed Central  Google Scholar 

  8. Polito, V. A. et al. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol. Med. 6, 1142–1160 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Parr, C. et al. Glycogen synthase kinase 3 inhibition promotes lysosomal biogenesis and autophagic degradation of the amyloid-β precursor protein. Mol. Cell. Biol. 32, 4410–4418 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Xiao, Q. et al. Neuronal-targeted TFEB accelerates lysosomal degradation of APP, reducing Aβgeneration and amyloid plaque pathogenesis. J. Neurosci. 35, 12137–12151 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Xu, Y. et al. TFEB regulates lysosomal exocytosis of tau and its loss of function exacerbates tau pathology and spreading. Mol. Psychiatry 26, 5925–5939 (2021).

    CAS  PubMed  Google Scholar 

  12. Martini-Stoica, H. et al. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J. Exp. Med. 215, 2355–2377 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Mindell, J. A. Lysosomal acidification mechanisms. Annu Rev. Physiol. 74, 69–86 (2012).

    CAS  PubMed  Google Scholar 

  14. Bouché, V. et al. Drosophila Mitf regulates the V-ATPase and the lysosomal-autophagic pathway. Autophagy 12, 484–498 (2016).

    PubMed  PubMed Central  Google Scholar 

  15. Zhang, T. et al. Mitf is a master regulator of the v-ATPase, forming a control module for cellular homeostasis with v-ATPase and TORC1. J. Cell Sci. 128, 2938–2950 (2015).

    PubMed Central  Google Scholar 

  16. Xu, Y., Martini-Stoica, H. & Zheng, H. A seeding based cellular assay of tauopathy. Mol. Neurodegener. 11, 32 (2016).

    PubMed  PubMed Central  Google Scholar 

  17. Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017).

    CAS  PubMed  Google Scholar 

  18. Krasemann, S. et al. The TREM2-APOEpathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581.e569 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Pastore, N. et al. TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages. Autophagy 12, 1240–1258 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Settembre, C. et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31, 1095–1108 (2012).

    CAS  PubMed Central  Google Scholar 

  21. Martina, J. A., Chen, Y., Gucek, M. & Puertollano, R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8, 903–914 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Roczniak-Ferguson, A. et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal 5, ra42 (2012).

    PubMed  PubMed Central  Google Scholar 

  23. Zeng, J., Shirihai, O. S. & Grinstaff, M. W. Degradable nanoparticles restore lysosomal pH and autophagic flux in lipotoxic pancreatic beta cells. Adv. Health. Mater. 8, e1801511 (2019).

    Google Scholar 

  24. Martini-Stoica, H., Xu, Y., Ballabio, A. & Zheng, H. The autophagy-lysosomal pathway in neurodegeneration: a TFEB perspective. Trends Neurosci. 39, 221–234 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Martina, J. A., Diab, H. I., Brady, O. A. & Puertollano, R. TFEB and TFE3 are novel components of the integrated stress response. EMBO J. 35, 479–495 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Brady, O. A., Martina, J. A. & Puertollano, R. Emerging roles for TFEB in the immune response and inflammation. Autophagy 14, 181–189 (2018).

    CAS  PubMed  Google Scholar 

  27. Toei, M., Saum, R. & Forgac, M. Regulation and isoform function of the V-ATPases. Biochemistry 49, 4715–4723 (2010).

    CAS  Google Scholar 

  28. Ho, M. N. et al. VMA13 encodes a 54-kDa vacuolar H(+)-ATPase subunit required for activity but not assembly of the enzyme complex in Saccharomyces cerevisiae. J. Biol. Chem. 268, 18286–18292 (1993).

    CAS  PubMed  Google Scholar 

  29. Jefferies, K. C. & Forgac, M. Subunit H of the vacuolar (H+) ATPase inhibits ATP hydrolysis by the free V1 domain by interaction with the rotary subunit F. J. Biol. Chem. 283, 4512–4519 (2008).

    CAS  PubMed  Google Scholar 

  30. Duan, X. et al. Deficiency of ATP6V1H causes bone loss by inhibiting bone resorption and bone formation through the TGF-β1 pathway. Theranostics 6, 2183–2195 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee, S. H. et al. v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat. Med. 12, 1403–1409 (2006).

    CAS  PubMed  Google Scholar 

  32. Hu, H. et al. Genome-wide association study identified ATP6V1H locus influencing cerebrospinal fluid BACE activity. BMC Med. Genet. 19, 75 (2018).

    PubMed  PubMed Central  Google Scholar 

  33. Duan, X., Yang, S., Zhang, L. & Yang, T. V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis. Theranostics 8, 5379–5399 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Fisher, D. E., Carr, C. S., Parent, L. A. & Sharp, P. A. TFEB has DNA-binding and oligomerization properties of a unique helix-loop-helix/leucine-zipper family. Genes Dev. 5, 2342–2352 (1991).

    CAS  PubMed  Google Scholar 

  35. Hemesath, T. J. et al. microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev. 8, 2770–2780 (1994).

    CAS  PubMed  Google Scholar 

  36. Dolan, M.-J. et al. A resource for generating and manipulating human microglial states in vitro. Preprint at bioRxiv https://doi.org/10.1101/2022.05.02.490100 (2022).

  37. Shi, Y. et al. Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms. Neuron 109, 2413–2426.e2417 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Udeochu, J. C. et al. Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience. Nat. Neurosci. 26, 737–750 (2023).

    CAS  PubMed Central  Google Scholar 

  39. Gratuze, M. et al. TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4. Neuron 111, 202–219.e207 (2023).

    CAS  PubMed  Google Scholar 

  40. Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663.e613 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Düvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).

    PubMed  PubMed Central  Google Scholar 

  43. Weichhart, T., Hengstschläger, M. & Linke, M. Regulation of innate immune cell function by mTOR. Nat. Rev. Immunol. 15, 599–614 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kierans, S. J. & Taylor, C. T. Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology. J. Physiol. 599, 23–37 (2021).

    CAS  PubMed  Google Scholar 

  45. Weichhart, T. et al. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29, 565–577 (2008).

    CAS  PubMed  Google Scholar 

  46. Wang, C. et al. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nat. Commun. 13, 1969 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Chen, X. et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature 615, 668–677 (2023).

    CAS  PubMed  Google Scholar 

  48. Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).

    CAS  PubMed  Google Scholar 

  49. Bassett, A. R., Tibbit, C., Ponting, C. P. & Liu, J. L. Highly efficient targeted mutagenesis of Drosophila with the CRISPR/Cas9 system. Cell Rep. 4, 220–228 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Martin, M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 17, 10–12 (2011).

    Google Scholar 

  51. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    CAS  PubMed  Google Scholar 

  52. Martina, J. A., Jeong, E. & Puertollano, R. p38 MAPK-dependent phosphorylation of TFEB promotes monocyte-to-macrophage differentiation. EMBO Rep. 24, e55472 (2023).

    CAS  PubMed  Google Scholar 

  53. Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).

    CAS  PubMed Central  Google Scholar 

  54. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    PubMed  PubMed Central  Google Scholar 

  55. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

    PubMed  PubMed Central  Google Scholar 

  56. Ramírez, F., Dündar, F., Diehl, S., Grüning, B. A. & Manke, T. deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 42, W187–W191 (2014).

    PubMed  PubMed Central  Google Scholar 

  57. Li, H. et al. Fly Cell Atlas: a single-nucleus transcriptomic atlas of the adult fruit fly. Science 375, eabk2432 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Lian, H., Roy, E. & Zheng, H. Protocol for primary microglial culture preparation. Bio Protoc. 6, e1989 (2016).

    Google Scholar 

  59. Bourdenx, M. et al. Nanoparticles restore lysosomal acidification defects: implications for Parkinson and other lysosomal-related diseases. Autophagy 12, 472–483 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to the Baylor College of Medicine Knockout Mouse Phenotyping Program (KOMP2) and the Genetically Engineered Rodent Models Core for the creation of CL and VKO mice and Cytometry and Cell Sorting Core for FACS analysis. We thank A. Cole, B. Reeves and B. Contreras for expert technical support and members of the Zheng laboratory for stimulating discussions. H.L. is a CPRIT Scholar in Cancer Research (RR200063). This study was supported by grants from the NIH (P01 AG066606, RF1 NS093652, RF1 AG020670 and RF1 AG062257 to H.Z. and R00 AG062746 to H.L.) and CureAlz Fund (to H.Z.).

Author information

Authors and Affiliations

Authors

Contributions

B.W., H.M.-S. and H.Z. conceived the project. M.S. and H.L. provided input and expertise in CL mutagenesis and snRNA-seq respectively. H.M.-S. performed bulk brain RNA-seq, created CL mice and was responsible for initial set of cell and mouse experiments. B.W. carried out follow-up molecular, cellular and biochemical analyses and worked with C.Q., T.-C.L., Y.Q. and H.L. in the snRNA-seq experiments and data analysis. S.W. assisted in mouse breeding and biochemical analysis, W.X. constructed acidic nanoparticles and Y.X. performed the seeding experiment. B.W., H.M.-S. and C.Q. prepared the figures, and B.W. and H.Z. wrote the manuscript. All authors read, edited and approved the final manuscript.

Corresponding author

Correspondence to Hui Zheng.

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Nature Neuroscience thanks Aimee Kao and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Lysosomal and immune pathway genes are enriched in 9-month-old Tau mice.

a, b. Volcano plots showing differentially expressed genes (DEGs) in Tau mice compared with WT mice at 4 and 9 months of age, respectively. Sample information, raw and unique mapped reads are shown in Supplementary Table 1. c, d. Snapshots of genome browser tracks of bulk brain RNA-seq of WT and Tau mice at 4 or 9 months at the Ctsd loci. e, f. qPCR analysis of hippocampal samples showing TFEB and TFEB regulated lysosomal genes are upregulated in 9 month-old but not 4 month-old Tau mice. Data are presented as average ± SEM. Two-tailed Student’s t-test. N = 4 samples/group for (e). In (f), N = 4 samples/group (Tfeb, Mucoln, Ctsb) and N = 5 samples/group (Ctsd, Ctsa, Lamp1).

Extended Data Fig. 2 snRNA-seq characterization of microglia subtypes.

a. UMAP plots of 55,254 cells from hippocampus of WT and Tau mice after batch effect corrections including batch, sex and genotype. b. UMAP representation of reclustered microglia from WT and Tau mice analyzed by snRNA-seq. The expression levels of homeostatic microglia genes (P2ry12, Ccr5 and Siglech), disease-associated-microglia genes (Apoe, Axl and Csf1) and IFN responsive-microglia genes (Oasl2, Ifi204 and Ifi207) are displayed. Sample information, mean UMI per cell and cell number per library are shown in Supplementary Table 2.

Extended Data Fig. 3 Atp6v1h gene promoter contains strong TFEB binding sites with two tandem CLEAR sequences.

Snapshots of normalized TFEB ChIP-Seq at locus of TFEB targets (ATP6V1H, ATP6V1B2, ATP6V1C1, ATP6V1G1, ATP6V1F, ATP6V0D1, ATP6V1E1, ATP6V0C, ATP6V1A, ATP6V1D). TFEB peaks are highlighted in orange box. CLEAR motifs which are zoomed-in within TFEB binding sites are marked by black lines.

Extended Data Fig. 4 Atp6v1h heterozygous deletion does not affect lysosomal acidification or degradative capacity.

a. qPCR analysis of Atp6v1h transcripts in 9-month-old hippocampal tissues of WT and Atp6v1h heterozygous knockout (VKO). N = 4/group. b. Western blot with quantification of ATP6V1H protein levels in forebrain lysates of 9-month-old WT and VKO mice. N = 3/group. c. Representative images of LysoSensor Green DND-189 fluorescence in WT and VKO primary glial cultures. Bafilomycin (Baf) and NH4Cl treated WT cultures were used as controls. Scale bar: 10 µm. d. Quantification of (c) showing comparable levels of lysosomal acidification in VKO and WT cultures. N = 8 (WT; VKO); N = 6 (Baf); N = 7 (NH4CL). e. Representative images of DQ-BSA fluorescence co-stained with LAMP1 in WT and VKO primary glial cultures. Bafilomycin (Baf) treated WT cultures were used as a control. Scale bar: 10 µm. f. Quantification of (e) showing normal lysosomal degradation capacity in VKO cultures. N = 10/group. Data are presented as average ± SEM. Two-tailed t-test (a,b) and one-way ANOVA with Sidak’s correction (d,f).

Source data

Extended Data Fig. 5 Reduced astrogliosis in Tau;CL mice.

Representative fluorescent confocal images of GFAP and AT8 immunostaining (a) with quantification (b) in the dentate gyrus of 9-month-old Tau and Tau;CL mice. Scale bar: 50 µm and 25 µm in brackets. N = 9/group. Data are presented as average ± SEM. Two-tailed Student’s t-test.

Extended Data Fig. 6 Atp6v1h heterozygous deletion does not affect tau histopathology or gliosis.

a. Representative fluorescent confocal images of AT8, Iba1 and GFAP in the dentate gyrus of 9-month-old WT, VKO, Tau and Tau;VKO. Scale bar: 50 μm. N = 8/group. b–d. Quantification of (a). e. Representative MCI fluorescent confocal images in the dentate gyrus of 9-month-old Tau and Tau;VKO mice. Scale bar: 50 μm. N = 8/group. f. Quantification of (e). g, h. Western blot (g) with quantification (h) of total and phospho-tau species recognized by CP13 and PHF1antibodies. Samples were derived from forebrain lysates of 9-month-old WT, VKO, Tau and Tau;VKO. N = 5/group. i,j. qPCR analysis of Tnfa and Il1b in 9-month-old WT, VKO, Tau and Tau;VKO hippocampal tissues. N = 4 (WT and VKO); N = 5 (Tau and Tau;VKO). Data are presented as average ± SEM. Two-tailed t-test (b,c,d,h,f) and one-way ANOVA with Sidak’s correction (i,j). Tau vs. Tau;VKO: non-significant.

Source data

Extended Data Fig. 7 Acidic nanoparticles are targeted to the lysosomes.

Confocal images showing Acidic nanoparticles (AN) co-localized with Lamp1-marked lysosomes in microglia culture. This experiment was repeated 3 times. Scale bar: 10 µm.

Extended Data Fig. 8 snRNA-seq analysis of hippocampus from WT, Tau, CL and Tau;CL mice.

a. UMAP plots of 137,734 cells from the hippocampus of WT, Tau, CL and Tau;CL mice after batch effect corrections including batch, sex and genotype. b. UMAP plots of 137,734 cells from hippocampus across each genotype. c. UMAP plots of re-clustered microglia cells in female (orange) and male (blue) across genotypes. Sample information, mean UMI per cell and cell number per library are shown in Supplementary Table 2.

Extended Data Fig. 9 Reduced lysosomal and inflammatory pathway genes in Tau;CL microglia.

a. Differentially expressed genes analysis in CL versus WT microglia. Volcano plots showing DEGs for all microglia populations in CL versus WT mice. Up-regulated genes are highlighted in red; Down-regulated genes are highlighted in blue. b. Volcano plots showing DEGs for all microglia in Tau;CL versus WT genotype mice. Up-regulated genes are highlighted in red; Down-regulated genes are highlighted in blue. c. GO enrichment analysis for up-regulated DEGs in Tau;CL vs WT comparing with Tau vs WT. Hypergeometric test was used to identify significant enrichment pathways; FDR < 0.01.

Extended Data Fig. 10 Analysis HIF-1a inhibitor Chrysin treatment in microglia cultures.

a. Representative images of HIF-1α immunofluorescence in primary microglia cultures treated with hypoxia-mimetic CoCl2 alone or co-treated with the HIF-1α inhibitor Chrysin. Scale bar: 20 µm. b. Quantification of (a) showing CoCl2 enhanced HIF-1α protein levels, which were abolished by Chrysin cotreatment. N = 3 independent experiments. c–d. qPCR analysis of the expression of HIF-1α downstream target genes Vegf and Pgk1. N = 3 independent experiments. Data are presented as average ± SEM. One-way ANOVA with Sidak’s correction (b,c,d).

Supplementary information

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Source Data Fig. 5

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Source Data Extended Data Fig. 4

Unprocessed Western Blots.

Source Data Extended Data Fig. 6

Unprocessed Western Blots.

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Wang, B., Martini-Stoica, H., Qi, C. et al. TFEB–vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy. Nat Neurosci 27, 48–62 (2024). https://doi.org/10.1038/s41593-023-01494-2

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