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p(HGNC:MAPT, var("p.Pro301Ser"))

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Entity

Name
MAPT
Namespace
hgnc
Namespace Version
20180906
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns

Appears in Networks 3

Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways v1.0.1

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

Alzheimer's disease pathological lesions activate the spleen tyrosine kinase. v1.0.0

In-Edges 26

a(CHEBI:"cytochalasin D") decreases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Entry of monomeric tau was markedly reduced in the presence of 1 mM Cytochalasin D, as reflected in the 95% reduction in the number of monomeric tau-pHrodo-positive objects after 3-hr incubation in the presence of 1 mMCytochalasinD (Figure 5C) PubMed:29590627

Appears in Networks:

a(CHEBI:dynasore) decreases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

The amount of monomeric tau entering neurons, as measured by total fluorescent intensity of intracellular monomeric tau-pHrodo vesicles, was significantly reduced by dynamin inhibition, as shown at 1 and 3 hr after the addition of extracellular tau (Figure 4B) PubMed:29590627

Appears in Networks:

a(CHEBI:heparin) causesNoChange tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

We confirmed that heparin within the aggregated tau preparations did not contribute to tau entry into neurons, finding that uptake of both monomeric and aggregated tau was unaffected in the presence of heparin (Figures S4C and S4D PubMed:29590627

Appears in Networks:

a(GO:"early endosome") association p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

As early as 1 hr after the addition of extracellular tau, monomeric and aggregated tau-Dylight were co-localized in EEA1+ early endosomes PubMed:29590627

Appears in Networks:

a(GO:"late endosome") association p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

Monomeric and aggregated tau-Dylight were also detected in LAMP1+late endosomes and lysosomes, consistent with endocytosed proteins first reaching early endosomes, before late endosomes and lysosomes PubMed:29590627

Appears in Networks:

a(GO:lysosome) association p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

Monomeric and aggregated tau-Dylight were also detected in LAMP1+late endosomes and lysosomes, consistent with endocytosed proteins first reaching early endosomes, before late endosomes and lysosomes PubMed:29590627

Appears in Networks:

a(GO:lysosome) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Thus, monomeric and aggregated tau both efficiently enter neurons via the endosome/lysosome system, and they are actively trafficked within vesicles over long distances within neurons over several hours PubMed:29590627

Appears in Networks:

bp(GO:endocytosis) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Thus, monomeric and aggregated tau both efficiently enter neurons via the endosome/lysosome system, and they are actively trafficked within vesicles over long distances within neurons over several hours PubMed:29590627

Appears in Networks:

composite(a(CHEBI:"cytochalasin D"), p(HGNC:MAPT, var("p.Pro301Ser"))) hasComponent p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

Appears in Networks:

composite(a(CHEBI:"cytochalasin D"), p(HGNC:MAPT, var("p.Pro301Ser"))) decreases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

These independent assays confirmed the same differential effects of the two inhibitors observed by live imaging of pHrodo-tau: at the 3-hr assay point, dynamin inhibition had no effect on the number of monomeric tau-Dylightpositive punctae within neurons, whereas inhibition of actin polymerization reduced the amount of intracellular tau by over half (Figure S6). PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

After extensive washing, monomeric and aggregated tau-Dylight were both detected within cells expressing the neuron-specific microtubule-associated protein MAP2, confirming that both forms of tau enter neurons PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

Tau-Dylight was found predominantly within the somatic compartment of neurons (Figure 1A) PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

After a 4-hr incubation with extracellular tau, flow cytometry analysis (Figures 1B and 1C) revealed that 83% and 73% of dissociated cells contained monomeric or aggregated tau-Dylight, respectively, demonstrating that extracellular tau efficiently enters human neurons in culture PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Internalization of monomeric tau (P301S) and wild-type tau was comparable and concentration dependent (Figure S3A), confirming that the P301S mutation does not confer the ability to efficiently enter neurons, nor is this form of tau likely to aggregate in extracellular media during the 3- to 4-hr incubation period PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Incubation of tau-pHrodo with human neurons at a range of concentrations from 2.5 to 25 nM (0.12–1.2 µg.mL-1, diluted in culture medium) showed that tau entry to neurons is rapid, as visualized by live imaging PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

We found that FLAG-tagged tau enters neurons efficiently and that internalized tau persists at detectable levels within neurons for at least 4 days (Figure S4A) PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

Intracellular fluorescent punctae were observed within the first 10 min of exposure of neurons to monomeric tau-pHrodo (Figure 2A; Video S1). Tau-pHrodo-positive structures increased in size and intensity over the 4-hr course of the assay. These structures were present within neurites and accumulated in the cell bodies of neurons PubMed:29590627

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

In the presence of 15 and 25 nM monomeric tau-pHrodo, the number of tau-pHrodo-positive objects approached a plateau (>90% of final measurement) after approximately 1 hr (Figure 2C) PubMed:29590627

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

These kinetics of aggregated tau-pHrodo entry are similar to that of both lower concentrations of monomeric tau (2.5 nM) and of low-molecular weight (10-kDa) dextran-pHrodo (same molarity as monomeric tau samples; Figures S5A–S5C PubMed:29590627

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

In agreement with the monomeric tau-pHrodo experiments, monomeric tau-Dylight was rapidly taken up into neurons (Figure 3C PubMed:29590627

Appears in Networks:

p(HGNC:MAPT) hasVariant p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

Appears in Networks:

composite(a(CHEBI:dynasore), p(HGNC:MAPT, var("p.Pro301Ser"))) hasComponent p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

Appears in Networks:

composite(a(CHEBI:dynasore), p(HGNC:MAPT, var("p.Pro301Ser"))) causesNoChange tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

These independent assays confirmed the same differential effects of the two inhibitors observed by live imaging of pHrodo-tau: at the 3-hr assay point, dynamin inhibition had no effect on the number of monomeric tau-Dylightpositive punctae within neurons, whereas inhibition of actin polymerization reduced the amount of intracellular tau by over half (Figure S6). PubMed:29590627

Appears in Networks:

act(p(HGNC:DNM1)) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

The amount of monomeric tau entering neurons, as measured by total fluorescent intensity of intracellular monomeric tau-pHrodo vesicles, was significantly reduced by dynamin inhibition, as shown at 1 and 3 hr after the addition of extracellular tau (Figure 4B) PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 202)) positiveCorrelation p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration. PubMed:24406748

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Thr, 205)) positiveCorrelation p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration. PubMed:24406748

Appears in Networks:

Out-Edges 22

p(HGNC:MAPT, var("p.Pro301Ser")) increases path(MESH:"Frontotemporal Dementia") View Subject | View Object

We used the tau P301S variant, an autosomal dominant mutation that causes early onset FTD with high penetrance (Bugiani et al., 1999; Guo et al., 2017) PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

After extensive washing, monomeric and aggregated tau-Dylight were both detected within cells expressing the neuron-specific microtubule-associated protein MAP2, confirming that both forms of tau enter neurons PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

Tau-Dylight was found predominantly within the somatic compartment of neurons (Figure 1A) PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

After a 4-hr incubation with extracellular tau, flow cytometry analysis (Figures 1B and 1C) revealed that 83% and 73% of dissociated cells contained monomeric or aggregated tau-Dylight, respectively, demonstrating that extracellular tau efficiently enters human neurons in culture PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Internalization of monomeric tau (P301S) and wild-type tau was comparable and concentration dependent (Figure S3A), confirming that the P301S mutation does not confer the ability to efficiently enter neurons, nor is this form of tau likely to aggregate in extracellular media during the 3- to 4-hr incubation period PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Incubation of tau-pHrodo with human neurons at a range of concentrations from 2.5 to 25 nM (0.12–1.2 µg.mL-1, diluted in culture medium) showed that tau entry to neurons is rapid, as visualized by live imaging PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

We found that FLAG-tagged tau enters neurons efficiently and that internalized tau persists at detectable levels within neurons for at least 4 days (Figure S4A) PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

Intracellular fluorescent punctae were observed within the first 10 min of exposure of neurons to monomeric tau-pHrodo (Figure 2A; Video S1). Tau-pHrodo-positive structures increased in size and intensity over the 4-hr course of the assay. These structures were present within neurites and accumulated in the cell bodies of neurons PubMed:29590627

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

In the presence of 15 and 25 nM monomeric tau-pHrodo, the number of tau-pHrodo-positive objects approached a plateau (>90% of final measurement) after approximately 1 hr (Figure 2C) PubMed:29590627

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

These kinetics of aggregated tau-pHrodo entry are similar to that of both lower concentrations of monomeric tau (2.5 nM) and of low-molecular weight (10-kDa) dextran-pHrodo (same molarity as monomeric tau samples; Figures S5A–S5C PubMed:29590627

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

In agreement with the monomeric tau-pHrodo experiments, monomeric tau-Dylight was rapidly taken up into neurons (Figure 3C PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) association a(GO:"early endosome") View Subject | View Object

As early as 1 hr after the addition of extracellular tau, monomeric and aggregated tau-Dylight were co-localized in EEA1+ early endosomes PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) association a(GO:"late endosome") View Subject | View Object

Monomeric and aggregated tau-Dylight were also detected in LAMP1+late endosomes and lysosomes, consistent with endocytosed proteins first reaching early endosomes, before late endosomes and lysosomes PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) association a(GO:lysosome) View Subject | View Object

Monomeric and aggregated tau-Dylight were also detected in LAMP1+late endosomes and lysosomes, consistent with endocytosed proteins first reaching early endosomes, before late endosomes and lysosomes PubMed:29590627

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration. PubMed:24406748

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration. PubMed:24406748

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases path(MESH:"Frontotemporal Dementia") View Subject | View Object

We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration. PubMed:24406748

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) decreases bp(GO:"axonal transport") View Subject | View Object

We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration. PubMed:24406748

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) decreases path(MESH:Cognition) View Subject | View Object

We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration. PubMed:24406748

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Hippocampal neurons of Tg Tau P301S mice exhibit a high level of tau hyperphosphorylation (Fig. 4b) as well as an accumulation of pathogenic tau conformers (MC1, not shown) compared to WT littermates (Fig. 4a). PubMed:28877763

Appears in Networks:
Annotations
Cell Ontology (CL)
hippocampal neuron

p(HGNC:MAPT, var("p.Pro301Ser")) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Cortical neurons of Tg Tau P301S mice also exhibit an increased level of tau hyperphosphorylation (Fig. 5b) compared to wild-type littermates (Fig. 5a). PubMed:28877763

Appears in Networks:
Annotations
Cell Ontology (CL)
cerebral cortex neuron

p(HGNC:MAPT, var("p.Pro301Ser")) increases a(HBP:"Tau aggregates") View Subject | View Object

Hippocampal neurons of Tg Tau P301S mice exhibit a high level of tau hyperphosphorylation (Fig. 4b) as well as an accumulation of pathogenic tau conformers (MC1, not shown) compared to WT littermates (Fig. 4a). PubMed:28877763

Appears in Networks:
Annotations
Cell Ontology (CL)
hippocampal neuron

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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.