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PubMed: 30108137

Title
TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading.
Journal
The Journal of experimental medicine
Volume
215
Issue
None
Pages
2355-2377
Date
2018-09-03
Authors
Bajaj L | Chen F | Zheng H | Martini-Stoica H | Lee VMY | Cole AL | Swartzlander DB | Wan YW | Sardiello M | Liu Z | Bader DA | Trojanowski JQ

Evidence 7b5d1dc3b8
JSON

Transcriptomic analysis of these isolated astrocytes revealed an increase in TFEB tran- scripts, as well as transcripts of several of its well-known target genes in the rTg4510 relative to wild-type controls

a(MESH:Astrocytes) increases p(MGI:Tfeb) View Subject | View Object

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Evidence 1ad8ab3a15
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In addition, flow cytometry analysis demonstrated that heparin reduces dye-conjugated pff uptake in both TFEB and EGFP transduced astrocytes, suggesting that macropino- cytosis is responsible for astroglial pff uptake

act(a(MESH:Astrocytes)) increases a(HBP:"Tau fibrils") View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte

bp(MESH:Pinocytosis) increases act(a(MESH:Astrocytes)) View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte

Evidence 0e65a2e6ef
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Inhibiting mTORC1 blocks the phosphor- ylation of TFEB, allowing unphosphorylated TFEB to translocate to the nucleus and become transcriptionally active

p(FPLX:mTORC1) increases p(MGI:Tfeb, pmod(Ph)) View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte

Evidence 842b32752e
JSON

TFEB activation has been linked to lysosomal stress and the ac- cumulation of aberrant protein aggregates, indicated by TFEB’s nuclear localization in lysosomal storage disorders

p(HGNC:TFEB) decreases act(a(MESH:Lysosomes)) View Subject | View Object

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Evidence 1dcc848cde
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as expected, the expression of several TFEB lysosomal target genes was signifi- cantly up-regulated in TFEB-transduced astrocytes, including lysosomal marker LAMP1 and lysosomal proteases, cathepsins A and B

p(MGI:Tfeb) increases p(MGI:Lamp1) View Subject | View Object

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p(MGI:Tfeb) increases p(MGI:Ctsa) View Subject | View Object

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p(MGI:Tfeb) increases p(MGI:Ctsb) View Subject | View Object

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Evidence 6828afc688
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In sum, these results demonstrate that TFEB regulates the lysosomal pathway in primary astrocytes.

p(MGI:Tfeb) regulates act(a(MESH:Lysosomes)) View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte

Evidence b440887529
JSON

TFEB not only increased the proportion of cells taking up beads, but also increased the pro- portion of cells taking up multiple beads, suggesting an enhanced phagocytic capacity

p(MGI:Tfeb) increases act(a(MESH:Phagocytes)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte

Evidence 5d39cb7c9f
JSON

Our results demonstrate a statistically significant increase of 12% in the uptake of pffs in TFEB transduced astrocytes relative to control at the 1-h time point, with a 22% relative increase in up- take in the TFEB transduced cells at 4 h

p(MGI:Tfeb) increases a(HBP:"Tau fibrils") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte

Evidence fac9a7e544
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Flow cytometry revealed that Torin1 treatment of TFEB transduced astrocytes increased dye-conjugated pff uptake 63% relative to EGFP transduced controls as shown by median fluorescence in- tensity, while under basal conditions, the TFEB overexpressing astrocytes increased uptake just 18% relative to EGFP expressing controls (Fig. 2 K). Thus, TFEB enhances phagocytic pathways in astrocytes, in particular increasing the uptake of pffs.

p(MGI:Tfeb) increases a(HBP:"Tau fibrils") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte

p(MGI:Tfeb) increases bp(MESH:Phagocytosis) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte

Evidence b56d589d74
JSON

. Recapitulating the uptake assay with dye-conjugated pffs in TFEB KO astrocytes, we observed a modest reduction pff uptake compared with primary astrocytes from littermate controls

p(MGI:Tfeb) increases a(HBP:"Tau fibrils") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte

Evidence 962b9571f2
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In sum, these data suggest that TFEB stimulates uptake and trafficking of pffs to the lysosome for degradation.

p(MGI:Tfeb) increases tloc(a(HBP:"Tau fibrils")) View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte

Evidence d817d6763e
JSON

qRT-PCR demonstrated undetectable transcript levels of TFEB as well as a reduction in LAMP1 mRNA in TFEB KO astrocytes compared with littermate controls

p(MGI:Tfeb) increases r(MGI:Lamp1) View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte

Evidence 183980f145
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Flow cytometry analysis of primary astrocytes incubated with DQ-BSA revealed an ∼60% increase in median fluorescence for TFEB-transduced astro- cytes, indicating that TFEB enhances uptake and proteolysis of DQ-BSA

p(MGI:Tfeb) increases bp(MESH:Proteolysis) View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte

Evidence a70fc00729
JSON

Immunoblot- ting for total tau and phospho-tau antibodies, PHF1 and CP13, demonstrated no statistical difference in hippocampal brain ly- sate from TFEB- versus EGFP-injected rTg4510 male or female mice

p(MGI:Tfeb) causesNoChange p(MGI:Phf1) View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte

Evidence dfb73bf718
JSON

Western blot a reduction in phospho-tau species recognized by AT8 (trending), AT180, and CP13 antibodies in the TFEB-injected mice

p(MGI:Tfeb) decreases p(MGI:Mapt, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte

Evidence 37bd022ebc
JSON

In the insoluble fraction, phospho- and total tau species were all reduced in the TFEB mice, as demonstrated by Western blot

p(MGI:Tfeb) decreases p(MGI:Mapt, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte

p(MGI:Tfeb) decreases p(MGI:Mapt) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte

Evidence 0a191ac779
JSON

Quantifying the area fluorescence of MC1 staining for both hippocampi from sections representing the entire volume of hippocampus showed that astroglial TFEB had no impact on MC1 staining on the ipsi- lateral side, but significantly reduced the area of MC1 staining on the contralateral side

p(MGI:Tfeb) causesNoChange p(MGI:Mapt, pmod(Ph)) View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte
MeSH
Hippocampus

Evidence cf492fcd88
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Overall, these results show that astroglial TFEB overexpression reduces tau pathology and gliosis in the hippocampus of PS19 tauopathy mice.

p(MGI:Tfeb) decreases path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte
MeSH
Hippocampus

p(MGI:Tfeb) decreases path(MESH:Gliosis) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte
MeSH
Hippocampus

Evidence 4b38de6fca
JSON

Transcriptional levels of TFEB and several of its well-known lysosomal targets were stratified by no demen- tia, mild cognitive impairment, and dementia,these transcript levels positively correlate with cognitive decline

path(MESH:"Cognitive Dysfunction") positiveCorrelation r(HGNC:TFEB) View Subject | View Object

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r(HGNC:TFEB) positiveCorrelation path(MESH:"Cognitive Dysfunction") View Subject | View Object

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Evidence e4af580773
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. In addition, human brains diagnosed with frontotemporal demen- tia (FTD) demonstrated an increase in transcriptional levels of TFEB and TFEB lysosomal target gene LAMP1

path(MESH:"Frontotemporal Dementia") increases r(HGNC:TFEB) View Subject | View Object

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path(MESH:"Frontotemporal Dementia") increases r(HGNC:LAMP1) View Subject | View Object

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Evidence 4bf28d3c61
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On the protein level, TFEB lysosomal target genes LAMP1 and Cathep- sin D (CTSD) are also increased in the FTD frontal cortex relative to normal subjects, and TFEB protein levels trended increased with statistical significance in the CBD group

path(MESH:"Frontotemporal Dementia") increases p(HGNC:TFEB) View Subject | View Object

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path(MESH:"Frontotemporal Dementia") increases p(HGNC:CTSD) View Subject | View Object

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Evidence 9b08715c6c
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In the rTg4510 mouse model of tauopathy (Ramsden et al., 2005; SantaCruz et al., 2005), gene set enrichment analysis (GSEA) of microarray data revealed a similar enrichment of TFEB’s tran- scriptional profile when comparing 4-mo-old transgenic mice with widespread NFTs to wild-type mice, indicating TFEB’s activation with tau pathology (Fig. 1 F).

path(MESH:Tauopathies) increases p(MGI:Tfeb) View Subject | View Object

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Evidence 0232b285c4
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Examining the protein levels in another tauopathy mouse model, hippocampal lysates from PS19 mice (Yoshiyama et al., 2007) at 10 mo of age showed increases in TFEB and lysosomal proteins LAMP1 and CTSD com- pared with wild-type mice (Fig. S1, G and H).

path(MESH:Tauopathies) increases p(MGI:Tfeb) View Subject | View Object

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path(MESH:Tauopathies) increases p(MGI:Lamp1) View Subject | View Object

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path(MESH:Tauopathies) increases p(MGI:Ctsd) View Subject | View Object

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