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PubMed: 29686391

Title
Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs).
Journal
Scientific reports
Volume
8
Issue
None
Pages
6382
Date
2018-04-23
Authors
See SK | Chen JJ | Miller GM | Rauch JN | Sorum AW | Kampmann M | Sharf T | Hsieh-Wilson LC | Kosik KS

Evidence d7885d8baf
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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)

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

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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

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

Appears in Networks:

Evidence 358f5bb52e
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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)

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

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

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Evidence 85c1b87b08
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Treatment of cells with an inhibitor for DNM2, Dynasore, was also able to reduce uptake of tau (Supplementary Fig. 2 f)

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

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Evidence 926759c8a9
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We found that internalization of tau can be efficiently competed by the presence of heparin or HS in the media (Fig. 4a)

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

Appears in Networks:

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

Appears in Networks:

Evidence a6f7f3ee67
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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)

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

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

Appears in Networks:

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

Appears in Networks:

Evidence e41b28a959
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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)

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

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a(CHEBI:palbociclib) decreases act(p(HGNC:CDK4)) View Subject | View Object

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a(CHEBI:palbociclib) decreases act(p(HGNC:CDK6)) View Subject | View Object

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

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

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Evidence cdb57024c9
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Removal of N-sulfates or 2-O-sulfates had little effect on tau binding (15.0 ± 5 nM and 7.4 ± 1.0 nM, respectively), while removal of all O-sulfates and, in particular 6-O-sulfates, led to a significant decrease in tau binding (>1 μM in each case; Fig. 3c,d)

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

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

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Evidence 2910fc2168
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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

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

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Annotations
MeSH
Neurons

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

Appears in Networks:
Annotations
MeSH
Neurons

Evidence 6aeea239d6
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Further, human iPS-derived neurons also showed a preference for smaller structures of tau, with fibrillized tau showing nearly no uptake (Fig. 1d)

a(HBP:"Tau fibrils") causesNoChange tloc(a(HBP:"Tau fibrils"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

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

Appears in Networks:
Annotations
MeSH
Neurons

Evidence 9b20bf0a8a
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Monomeric, oligomeric and sonicated fibrils were efficiently internalized, while fibril samples were not (Fig. 1c and Supplementary Fig. 1d)

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

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

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

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

Appears in Networks:

a(HBP:"sonicated tau fibrils") positiveCorrelation tloc(a(HBP:"sonicated tau fibrils"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Appears in Networks:

tloc(a(HBP:"sonicated tau fibrils"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) positiveCorrelation a(HBP:"sonicated tau fibrils") View Subject | View Object

Appears in Networks:

Evidence daca5faaf0
JSON

Tau protein can form multiple quaternary structures in solution, and recent evidence suggests that small tau oligomeric species may play a critical role in the spread of tau pathology and neurotoxicity

a(HBP:"Tau oligomers") positiveCorrelation path(MESH:Tauopathies) View Subject | View Object

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a(HBP:"Tau oligomers") positiveCorrelation bp(HBP:neurotoxicity) View Subject | View Object

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bp(HBP:neurotoxicity) positiveCorrelation a(HBP:"Tau oligomers") View Subject | View Object

Appears in Networks:

path(MESH:Tauopathies) positiveCorrelation a(HBP:"Tau oligomers") View Subject | View Object

Appears in Networks:

Evidence d8324ece62
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These single gene knockdowns repressed uptake of tau monomer by over 50% (Fig. 2b) and also reduced the uptake of tau oligomers (Fig. 2c)

bp(GO:"heparan sulfate proteoglycan biosynthetic process") association p(HGNC:EXT2) View Subject | View Object

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bp(GO:"heparan sulfate proteoglycan biosynthetic process") association p(HGNC:HS6ST1) View Subject | View Object

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

Appears in Networks:

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

Appears in Networks:

p(HGNC:EXT2) association bp(GO:"heparan sulfate proteoglycan biosynthetic process") View Subject | View Object

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

Appears in Networks:

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

Appears in Networks:

p(HGNC:HS6ST1) association bp(GO:"heparan sulfate proteoglycan biosynthetic process") View Subject | View Object

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

Appears in Networks:

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

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Evidence e0d41090cf
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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.

bp(GO:"mitotic G1 phase") positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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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

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bp(GO:endocytosis) positiveCorrelation bp(GO:"mitotic G1 phase") View Subject | View Object

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Evidence 4513e3a692
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The selective knockdown of genes such as TP53, led to a decrease in G1 length and thus an overall increase in cell proliferation (Supplementary Fig. 2d)

g(HGNC:TP53) increases bp(GO:"mitotic G1 phase") View Subject | View Object

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g(HGNC:TP53) decreases bp(GO:"cell proliferation") View Subject | View Object

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Evidence 1904960fb8
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Further, these gene knockdowns were sufficient to reduce the uptake of tau in iPS-derived neurons (Fig. 2d)

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

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

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

Appears in Networks:
Annotations
MeSH
Neurons

Evidence e9454b9209
JSON

Previous reports had indicated that internalization of tau could be regulated by HSPGs16, but our identification of HS6ST1, an enzyme that is responsible for 6-O-sulfation of HSPGs, supports a hypothesis that specific motifs on HSPGs might be important for tau uptake

p(HGNC:HS6ST1) increases a(HBP:"6-O-sulfated heparin") View Subject | View Object

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Evidence d40ecbeffa
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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)

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

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

Appears in Networks:

Evidence 99e0b6618d
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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)

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

Appears in Networks:

p(HGNC:SULF1) decreases a(HBP:"6-O-sulfated heparin") View Subject | View Object

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

Appears in Networks:

p(HGNC:SULF2) decreases a(HBP:"6-O-sulfated heparin") View Subject | View Object

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