diff --git a/hbp_knowledge/tau/evans2018.bel b/hbp_knowledge/tau/evans2018.bel index 03313a603..70852443f 100644 --- a/hbp_knowledge/tau/evans2018.bel +++ b/hbp_knowledge/tau/evans2018.bel @@ -70,6 +70,7 @@ DEFINE ANNOTATION TextLocation AS URL "https://arty.scai.fraunhofer.de/artifact ############## # Statements # ############## + SET Citation = {"PubMed", "29590627"} # monomeric tau: p(HGNC:MAPT,var("p.P301S")) @@ -77,20 +78,26 @@ SET Citation = {"PubMed", "29590627"} SET Evidence = "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)" +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -> path(MESH:"Frontotemporal Dementia") +UNSET Confidence SET Evidence = "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" +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) a(HBP:"Tau aggregates") -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "Tau-Dylight was found predominantly within the somatic compartment of neurons (Figure 1A)" #monomeric and aggregated tau-Dylight +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(GO:"cell body")) a(HBP:"Tau aggregates") -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(GO:"cell body")) +UNSET Confidence SET Evidence = "After a 4-hr incubation with extracellular tau, flow cytometry analysis (Figures 1B @@ -98,29 +105,37 @@ 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" -p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) -a(HBP:"Tau aggregates") -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +SET Confidence = "Medium" +p(HGNC:MAPT,var("p.Pro301Ser"), loc(GO:"extracellular region")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +a(HBP:"Tau aggregates", loc(GO:"extracellular region")) -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "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" +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) p(HGNC:MAPT) -> tloc(p(HGNC:MAPT),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "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" #tau P301S +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "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)" #tau P301S +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET MeSHAnatomy = {"Neurons","Neurites"} @@ -129,25 +144,33 @@ SET Evidence = "Intracellular fluorescent punctae were observed within the first 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" +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(GO:"cell body")) +UNSET Confidence SET Evidence = "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)" +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(GO:"cell body")) +UNSET Confidence SET Evidence = "Internalization of aggregated tau-pHrodo (Figure 2D) was also found to be concentration dependent (Figure 2E)" +SET Confidence = "High" a(HBP:"Tau aggregates") -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(GO:"cell body")) +UNSET Confidence SET Evidence = "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" +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(GO:"cell body")) a(HBP:"Tau aggregates") -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(GO:"cell body")) a(CHEBI:dextran) -> tloc(a(CHEBI:dextran)),fromLoc(GO:"extracellular region"),toLoc(GO:"cell body")) +UNSET Confidence UNSET MeSHAnatomy @@ -155,43 +178,56 @@ SET Evidence = "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" +SET Confidence = "High" a(CHEBI:heparin) cnc tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) a(CHEBI:heparin) cnc tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "In agreement with the monomeric tau-pHrodo experiments, monomeric tau-Dylight was rapidly taken up into neurons (Figure 3C" +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "As early as 1 hr after the addition of extracellular tau, monomeric and aggregated tau-Dylight were co-localized in EEA1+ early endosomes" +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -- a(GO:"early endosome") a(HBP:"Tau aggregates") -- a(GO:"early endosome") +UNSET Confidence SET Evidence = "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" +SET Confidence = "High" p(HGNC:MAPT,var("p.Pro301Ser")) -- a(GO:"late endosome") p(HGNC:MAPT,var("p.Pro301Ser")) -- a(GO:lysosome) a(HBP:"Tau aggregates") -- a(GO:"late endosome") a(HBP:"Tau aggregates") -- a(GO:lysosome) +UNSET Confidence SET Evidence = "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" +SET Confidence = "Medium" bp(GO:endocytosis) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) -a(GO:lysosome) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +act(a(GO:lysosome)) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) bp(GO:endocytosis) -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) -a(GO:lysosome) -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +act(a(GO:lysosome)) -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "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)" +SET Confidence = "Medium" # dynamin inhibition via Dynasore +a(CHEBI:dynasore) -| act(p(FPLX:DNM)) +act(p(FPLX:DNM)) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) a(CHEBI:dynasore) -| tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) -act(p(HGNC:DNM1)) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "The effect of dynamin inhibition on the entry of aggregated tau was more pronounced than on monomeric tau (Figures 4D–4F). @@ -199,40 +235,51 @@ The total fluorescent intensity of intracellular aggregated taupHrodo was consistently reduced by more than 70% at 1 and 3 hr after tau addition (Figure 4E), and the number of taupHrodo- positive objects was reduced by 95% (Figure 4F)" +SET Confidence = "Medium" a(CHEBI:dynasore) -| tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) -act(p(HGNC:DNM1)) -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +act(p(FPLX:DNM)) -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "These data indicate that, at the concentrations studied, aggregated tau enters neurons almost entirely via endocytosis" +SET Confidence = "High" bp(GO:endocytosis) -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "Inhibition of actin polymerization with Cytochalasin D disrupts several clathrin-independent endocytic processes, including bulk endocytosis/ macropinocytosis (Mooren et al., 2012)" +SET Confidence = "Medium" a(CHEBI:"cytochalasin D") -| bp(GO:"actin filament polymerization") -a(CHEBI:"cytochalasin D") negativeCorrelation bp(GO:"bulk synaptic vesicle endocytosis") -bp(GO:"actin filament polymerization") positiveCorrelation bp(GO:"bulk synaptic vesicle endocytosis") -a(CHEBI:"cytochalasin D") negativeCorrelation bp(GO:macropinocytosis) -bp(GO:"actin filament polymerization") positiveCorrelation bp(GO:macropinocytosis) +a(CHEBI:"cytochalasin D") -| bp(GO:"bulk synaptic vesicle endocytosis") +bp(GO:"actin filament polymerization") -> bp(GO:"bulk synaptic vesicle endocytosis") +a(CHEBI:"cytochalasin D") -| bp(GO:macropinocytosis) +bp(GO:"actin filament polymerization") -> bp(GO:macropinocytosis) +UNSET Confidence SET Evidence = "Disruption of actin polymerization has previously been shown to inhibit entry of fibrils formed of the tau repeat domain (Holmes et al., 2013)" +SET Confidence = "High" bp(GO:"actin filament polymerization") -> tloc(a(HBP:"Tau fibrils"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "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)" +SET Confidence = "High" a(CHEBI:"cytochalasin D") -| tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "In contrast, disruption of actin polymerization with Cytochalasin D had little effect on the entry of aggregated tau (total fluorescent intensity and number of objects; Figures 5D–5F; Figure S5)" +SET Confidence = "High" a(CHEBI:"cytochalasin D") cnc tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) - +UNSET Confidence SET Evidence = "These independent assays confirmed the same differential effects of the two inhibitors observed by @@ -240,35 +287,47 @@ 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)." +SET Confidence = "High" composite(a(CHEBI:dynasore),p(HGNC:MAPT,var("p.Pro301Ser"))) cnc tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) composite(a(CHEBI:"cytochalasin D"),p(HGNC:MAPT,var("p.Pro301Ser"))) -| tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "Conversely, dynamin inhibition significantly reduced the entry of aggregated tau, with no significant effects of Cytochalasin D (Figure S6) at this relatively high molar concent of aggregated tau" +SET Confidence = "Medium" a(CHEBI:dynasore) -| tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) -act(p(HGNC:DNM1)) -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +act(p(FPLX:DNM)) -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) a(CHEBI:"cytochalasin D") cnc tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "Pre-incubation with the polyclonal (anti-taupAb) tau antibody reduced the amount of monomeric tau that entered neurons as assessed by the number of monomeric tau-pHrodo-containing vesicles (Figure 6B; Figure S7)" +SET Confidence = "Medium" #anti-tau polyclonal antibody to the C-terminal half of tau -#composite(a(HBP:"tau polyclonal antibody"),p(HGNC:MAPT,var("p.Pro301Ser"))) -| tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +composite(a(HBP:"tau polyclonal antibody"),p(HGNC:MAPT,var("p.Pro301Ser"))) -| tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "Tau antibodies also reduced entry of aggregated tau uptake into human neurons (Figure 6C)" -#composite(a(HBP:"tau polyclonal antibody"),a(HBP:"Tau aggregates")) -| tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +SET Confidence = "Medium" +composite(a(HBP:"tau polyclonal antibody"),a(HBP:"Tau aggregates")) -| tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "In the presence of anti-taupAb, the number of aggregated tau-pHrodo vesicles was reduced by more than half (Figure 6D; Figure S7)" -#composite(a(HBP:"tau polyclonal antibody"),p(HGNC:MAPT,var("p.Pro301Ser"))) -| composite(p(HGNC:MAPT,var("p.Pro301Ser")),a(MESH:"Transport Vesicles")) +SET Confidence = "Medium" +composite(a(HBP:"tau polyclonal antibody"),p(HGNC:MAPT,var("p.Pro301Ser"))) -| complex(p(HGNC:MAPT,var("p.Pro301Ser")),a(MESH:"Transport Vesicles")) +UNSET Confidence SET Evidence = "These independent assays confirmed that tau-specific antibodies significantly reduced the amount of tau-Dylight entering neurons (Figure S7)" -#a(HBP:"tau polyclonal antibody") -| tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +SET Confidence = "Medium" +a(HBP:"tau polyclonal antibody") -| tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence SET Evidence = "To distinguish between these possibilities, we performed additional assays using preformed @@ -276,4 +335,6 @@ aggregated tau-Dylight-antibody complexes. After 3 hr of incubation, antibodies were detected in the fixed neurons with a secondary antibody specific to the host species (antirabbit polyclonal; Figure 7) and also imaged for tau-Dylight." -#complex(a(HBP:"tau polyclonal antibody"),a(HBP:"Tau aggregates")) -> tloc(a(HBP:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +SET Confidence = "Medium" +complex(a(HBP:"tau polyclonal antibody"),a(HBP:"Tau aggregates")) -> tloc(a(HBP:"tau polyclonal antibody"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons)) +UNSET Confidence