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Recurate evans2018 #279

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4c7c1ad
Recurate evans2018
Trusha6128 Jul 27, 2019
c592174
Recurate evans2018
Trusha6128 Jul 27, 2019
6418c75
Recurate evans2018
Trusha6128 Jul 31, 2019
ea29d0a
Merge branch 'master' into Recurate-evans2018
YojanaGadiya Aug 19, 2019
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80 changes: 73 additions & 7 deletions hbp_knowledge/tau/evans2018.bel
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Expand Up @@ -77,50 +77,69 @@ 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 = "Medium"
SET Cell = "neuron"
p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
a(CONSO:"Tau aggregates") -> tloc(a(CONSO:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
UNSET Cell
UNSET Confidence

SET Evidence = "Tau-Dylight was found predominantly within the somatic
compartment of neurons (Figure 1A)"
SET Confidence = "Medium"
SET Cell = "neuron"
#monomeric and aggregated tau-Dylight
p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(GO:"cell body"))
a(CONSO:"Tau aggregates") -> tloc(a(CONSO:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(GO:"cell body"))
UNSET Confidence
UNSET Cell

SET Evidence = "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"
SET Confidence = "High"
#in-vito study
p(HGNC:MAPT,var("p.Pro301Ser")) -> tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
a(CONSO:"Tau aggregates") -> tloc(a(CONSO:"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"
SET Confidence = "High"
#tau P301S
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)"
SET Confidence = "High"
#tau P301S
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"}

Expand All @@ -129,151 +148,198 @@ 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(CONSO:"Tau aggregates") -> tloc(a(CONSO:"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(CONSO:"Tau aggregates") -> tloc(a(CONSO:"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

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(CONSO:"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 = "Medium"
p(HGNC:MAPT,var("p.Pro301Ser")) -- a(GO:"early endosome")
a(CONSO:"Tau aggregates") -- a(GO:"early endosome")
composite(p(HGNC:MAPT,var("p.Pro301Ser")),a(CONSO:"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(CONSO:"Tau aggregates") -- a(GO:"late endosome")
a(CONSO:"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"
SET Cell = "neuron"
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))
bp(GO:endocytosis) -> tloc(a(CONSO:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
a(GO:lysosome) -> tloc(a(CONSO:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
UNSET Cell
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 = "High"
# dynamin inhibition via Dynasore
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).
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 = "High"
a(CHEBI:dynasore) -| tloc(a(CONSO:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
act(p(HGNC:DNM1)) -> tloc(a(CONSO:"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(CONSO:"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 = "High"
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)
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(CONSO:"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(CONSO:"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
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 = "High"
a(CHEBI:dynasore) -| tloc(a(CONSO:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
act(p(HGNC:DNM1)) -> tloc(a(CONSO:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
a(CHEBI:"cytochalasin D") cnc tloc(a(CONSO:"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 = "Low"
#anti-tau polyclonal antibody to the C-terminal half of tau
#composite(a(CONSO:"tau polyclonal antibody"),p(HGNC:MAPT,var("p.Pro301Ser"))) -| tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
#complex(a(CONSO:"Tau antibody, 4E4"),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(CONSO:"tau polyclonal antibody"),a(CONSO:"Tau aggregates")) -| tloc(a(CONSO:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
SET Confidence = "Low"
#complex(a(CONSO:"Tau antibody, 4E4"),a(CONSO:"Tau aggregates")) -| tloc(a(CONSO:"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(CONSO:"tau polyclonal antibody"),p(HGNC:MAPT,var("p.Pro301Ser"))) -| composite(p(HGNC:MAPT,var("p.Pro301Ser")),a(MESH:"Transport Vesicles"))
SET Confidence = "Low"
#complex(a(CONSO:"Tau antibody, 4E4"),p(HGNC:MAPT,var("p.Pro301Ser"))) -| composite(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(CONSO:"tau polyclonal antibody") -| tloc(p(HGNC:MAPT,var("p.Pro301Ser")),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
SET Confidence = "Low"
#a(CONSO:"Tau antibody, 4E4") -| 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
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(CONSO:"tau polyclonal antibody"),a(CONSO:"Tau aggregates")) -> tloc(a(CONSO:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
SET Confidence = "Low"
#complex(a(CONSO:"Tau antibody, 4E4"),a(CONSO:"Tau aggregates")) -> tloc(a(CONSO:"Tau aggregates"),fromLoc(GO:"extracellular region"),toLoc(MESH:Neurons))
UNSET Confidence