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a(HBP:"Tau isoform F (441 aa)")

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Entity

Name
Tau isoform F (441 aa)
Namespace
HBP
Namespace Version
20181128
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/7e4be528f12abd28be768b62402fba6e083eaf9e/export/hbp-names.belns

Appears in Networks 2

Analysis of Isoform-specific Tau Aggregates Suggests a Common Toxic Mechanism Involving Similar Pathological Conformations and Axonal Transport Inhibition v1.0.1

Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs) v1.0.1

In-Edges 33

a(HBP:"phosphatase-activating domain") positiveCorrelation a(HBP:"Tau isoform F (441 aa)") View Subject | View Object

As expected, monomer and aggregated samples of all six tau isoforms showed equal reactivity for TNT1 and TOC1 when the samples were denatured because this exposes the epitopes making them equally accessible (Student’s t-tests, for all comparisons p > 0.05; Fig. 3C–H) PubMed:27574109

Appears in Networks:

path(MESH:"Protein Aggregation, Pathological") positiveCorrelation a(HBP:"Tau isoform F (441 aa)") View Subject | View Object

hT40 showed the highest amount of light scattering compared to other 4R isoforms, and there were no differences between the different 3R isoforms PubMed:27574109

Appears in Networks:

a(CHEBI:"chondroitin sulfate") decreases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Likewise, addition of 2-O-desulfated heparin was able to reduce uptake, whereas 6-O-desulfated heparin or chondroitin sulfate (negative control) were significantly less effective at reducing uptake (Fig. 4a) PubMed:29686391

Appears in Networks:

a(CHEBI:"chondroitin sulfate") causesNoChange tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Chondroitin sulfate and 6-O-desulfated heparin incubation did not reduce the median fluorescence, verifying that 6-O-sulfation is also important for tau internalization ex vivo (Fig. 4d and Supplementary Fig. 3b) PubMed:29686391

Appears in Networks:

a(CHEBI:dynasore) decreases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Treatment of cells with an inhibitor for DNM2, Dynasore, was also able to reduce uptake of tau (Supplementary Fig. 2 f) PubMed:29686391

Appears in Networks:

a(CHEBI:heparin) association tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

We found that internalization of tau can be efficiently competed by the presence of heparin or HS in the media (Fig. 4a) PubMed:29686391

Appears in Networks:

a(CHEBI:heparin) decreases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Consistent with our previous results, incubation with heparin, heparan sulfate, or 2-O-desulfated heparin reduced uptake of tau as quantified by the median 488 fluorescence intensity (Fig. 4d) PubMed:29686391

Appears in Networks:

a(CHEBI:palbociclib) increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

In line with these observations a small molecule inhibitor of CDK4/6 that causes a stall in G1 phase (PD0332991) was sufficient to almost double the amount of tau taken up in H4 cells (Supplementary Fig. 2e) PubMed:29686391

Appears in Networks:

a(HBP:"2-O-sulfated heparin") increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Likewise, addition of 2-O-desulfated heparin was able to reduce uptake, whereas 6-O-desulfated heparin or chondroitin sulfate (negative control) were significantly less effective at reducing uptake (Fig. 4a) PubMed:29686391

Appears in Networks:

a(HBP:"2-O-sulfated heparin") increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Consistent with our previous results, incubation with heparin, heparan sulfate, or 2-O-desulfated heparin reduced uptake of tau as quantified by the median 488 fluorescence intensity (Fig. 4d) PubMed:29686391

Appears in Networks:

a(HBP:"6-O-sulfated heparin") increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Likewise, addition of 2-O-desulfated heparin was able to reduce uptake, whereas 6-O-desulfated heparin or chondroitin sulfate (negative control) were significantly less effective at reducing uptake (Fig. 4a) PubMed:29686391

Appears in Networks:

a(HBP:"6-O-sulfated heparin") association tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

These results were consistent when tested in iPS-derived neurons (Fig. 4b), demonstrating that the 6-O-sulfation motif is indeed a critical determinant for cellular tau entry PubMed:29686391

Appears in Networks:
Annotations
MeSH
Neurons

a(HBP:"6-O-sulfated heparin") increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Chondroitin sulfate and 6-O-desulfated heparin incubation did not reduce the median fluorescence, verifying that 6-O-sulfation is also important for tau internalization ex vivo (Fig. 4d and Supplementary Fig. 3b) PubMed:29686391

Appears in Networks:

a(HBP:"Tau isoform F (441 aa)") positiveCorrelation tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Monomeric, oligomeric and sonicated fibrils were efficiently internalized, while fibril samples were not (Fig. 1c and Supplementary Fig. 1d) PubMed:29686391

Appears in Networks:

tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) positiveCorrelation a(HBP:"Tau isoform F (441 aa)") View Subject | View Object

Monomeric, oligomeric and sonicated fibrils were efficiently internalized, while fibril samples were not (Fig. 1c and Supplementary Fig. 1d) PubMed:29686391

Appears in Networks:

a(HBP:"Tau isoform F (441 aa)") increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Further, human iPS-derived neurons also showed a preference for smaller structures of tau, with fibrillized tau showing nearly no uptake (Fig. 1d) PubMed:29686391

Appears in Networks:
Annotations
MeSH
Neurons

a(MESH:"Heparitin Sulfate") decreases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Consistent with our previous results, incubation with heparin, heparan sulfate, or 2-O-desulfated heparin reduced uptake of tau as quantified by the median 488 fluorescence intensity (Fig. 4d) PubMed:29686391

Appears in Networks:

bp(GO:"mitotic G1 phase") regulates tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Endocytosis is known to increase during G1 phase25; therefore, it seemed logical that cell cycle regulators that can shorten the G1 phase could reduce the amount of tau uptake and vice versa. PubMed:29686391

Appears in Networks:

complex(a(CHEBI:heparin), a(HBP:"Tau isoform F (441 aa)")) hasComponent a(HBP:"Tau isoform F (441 aa)") View Subject | View Object

Appears in Networks:

complex(a(HBP:"6-O-sulfated heparin"), a(HBP:"Tau isoform F (441 aa)")) hasComponent a(HBP:"Tau isoform F (441 aa)") View Subject | View Object

Appears in Networks:

complex(a(HBP:"Tau isoform F (441 aa)"), a(MESH:"Heparitin Sulfate")) hasComponent a(HBP:"Tau isoform F (441 aa)") View Subject | View Object

Appears in Networks:

p(HGNC:CDK4) decreases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

In line with these observations a small molecule inhibitor of CDK4/6 that causes a stall in G1 phase (PD0332991) was sufficient to almost double the amount of tau taken up in H4 cells (Supplementary Fig. 2e) PubMed:29686391

Appears in Networks:

p(HGNC:CDK6) decreases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

In line with these observations a small molecule inhibitor of CDK4/6 that causes a stall in G1 phase (PD0332991) was sufficient to almost double the amount of tau taken up in H4 cells (Supplementary Fig. 2e) PubMed:29686391

Appears in Networks:

p(HGNC:DNM2) increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

These single gene knockdowns repressed uptake of tau monomer by over 50% (Fig. 2b) and also reduced the uptake of tau oligomers (Fig. 2c) PubMed:29686391

Appears in Networks:

p(HGNC:DNM2) increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Further, these gene knockdowns were sufficient to reduce the uptake of tau in iPS-derived neurons (Fig. 2d) PubMed:29686391

Appears in Networks:
Annotations
MeSH
Neurons

p(HGNC:EXT2) increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

These single gene knockdowns repressed uptake of tau monomer by over 50% (Fig. 2b) and also reduced the uptake of tau oligomers (Fig. 2c) PubMed:29686391

Appears in Networks:

p(HGNC:EXT2) increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Further, these gene knockdowns were sufficient to reduce the uptake of tau in iPS-derived neurons (Fig. 2d) PubMed:29686391

Appears in Networks:
Annotations
MeSH
Neurons

p(HGNC:HS6ST1) increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

These single gene knockdowns repressed uptake of tau monomer by over 50% (Fig. 2b) and also reduced the uptake of tau oligomers (Fig. 2c) PubMed:29686391

Appears in Networks:

p(HGNC:HS6ST1) increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Further, these gene knockdowns were sufficient to reduce the uptake of tau in iPS-derived neurons (Fig. 2d) PubMed:29686391

Appears in Networks:
Annotations
MeSH
Neurons

p(HGNC:SULF1) decreases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Overexpression of these enzymes in H4 cells, showed a dramatic decrease in tau uptake with Sulf1 reducing uptake to 17 ± 9%, and Sulf2 reducing uptake to 36 ± 15% (Fig. 4e) PubMed:29686391

Appears in Networks:

p(HGNC:SULF1) decreases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Overexpression of the constructs was confirmed with immunocytochemistry and qPCR analysis (Fig. 4f and Supplementary Fig. 3d) and the ability of the enzymes to reduce 6-O sulfation on the cell surface was confirmed by HPLC (Supplementary Fig. 3e,f) PubMed:29686391

Appears in Networks:

p(HGNC:SULF2) decreases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Overexpression of these enzymes in H4 cells, showed a dramatic decrease in tau uptake with Sulf1 reducing uptake to 17 ± 9%, and Sulf2 reducing uptake to 36 ± 15% (Fig. 4e) PubMed:29686391

Appears in Networks:

p(HGNC:SULF2) decreases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Overexpression of the constructs was confirmed with immunocytochemistry and qPCR analysis (Fig. 4f and Supplementary Fig. 3d) and the ability of the enzymes to reduce 6-O sulfation on the cell surface was confirmed by HPLC (Supplementary Fig. 3e,f) PubMed:29686391

Appears in Networks:

Out-Edges 8

a(HBP:"Tau isoform F (441 aa)") positiveCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

hT40 showed the highest amount of light scattering compared to other 4R isoforms, and there were no differences between the different 3R isoforms PubMed:27574109

Appears in Networks:

a(HBP:"Tau isoform F (441 aa)") increases a(HBP:"Tau oligomers") View Subject | View Object

As expected, monomer and aggregated samples of all six tau isoforms showed equal reactivity for TNT1 and TOC1 when the samples were denatured because this exposes the epitopes making them equally accessible (Student’s t-tests, for all comparisons p > 0.05; Fig. 3C–H) PubMed:27574109

Appears in Networks:

a(HBP:"Tau isoform F (441 aa)") positiveCorrelation a(HBP:"phosphatase-activating domain") View Subject | View Object

As expected, monomer and aggregated samples of all six tau isoforms showed equal reactivity for TNT1 and TOC1 when the samples were denatured because this exposes the epitopes making them equally accessible (Student’s t-tests, for all comparisons p > 0.05; Fig. 3C–H) PubMed:27574109

Appears in Networks:

a(HBP:"Tau isoform F (441 aa)") positiveCorrelation tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Monomeric, oligomeric and sonicated fibrils were efficiently internalized, while fibril samples were not (Fig. 1c and Supplementary Fig. 1d) PubMed:29686391

Appears in Networks:

tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) positiveCorrelation a(HBP:"Tau isoform F (441 aa)") View Subject | View Object

Monomeric, oligomeric and sonicated fibrils were efficiently internalized, while fibril samples were not (Fig. 1c and Supplementary Fig. 1d) PubMed:29686391

Appears in Networks:

a(HBP:"Tau isoform F (441 aa)") increases tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Further, human iPS-derived neurons also showed a preference for smaller structures of tau, with fibrillized tau showing nearly no uptake (Fig. 1d) PubMed:29686391

Appears in Networks:
Annotations
MeSH
Neurons

tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) association a(CHEBI:heparin) View Subject | View Object

We found that internalization of tau can be efficiently competed by the presence of heparin or HS in the media (Fig. 4a) PubMed:29686391

Appears in Networks:

tloc(a(HBP:"Tau isoform F (441 aa)"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) association a(HBP:"6-O-sulfated heparin") View Subject | View Object

These results were consistent when tested in iPS-derived neurons (Fig. 4b), demonstrating that the 6-O-sulfation motif is indeed a critical determinant for cellular tau entry PubMed:29686391

Appears in Networks:
Annotations
MeSH
Neurons

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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.