1. Catalog
  2. Nodes
  3. p(MGI:Mapt, var("p.Pro301Leu"))

p(MGI:Mapt, var("p.Pro301Leu"))

Equivalencies: 0 | Classes: 0 | Children: 0 | Explore

Entity

Name
Mapt
Namespace
MGI
Namespace Version
20170725
Namespace URL
https://arty.scai.fraunhofer.de/artifactory/bel/namespace/mgi-mouse-genes/mgi-mouse-genes-20170725.belns

Appears in Networks 2

Interplay of pathogenic forms of human tau with different autophagic pathways v1.0.1

Tau protein aggregation is associated with cellular senescence in the brain v1.0.0

In-Edges 13

p(MGI:Mapt) hasVariant p(MGI:Mapt, var("p.Pro301Leu")) View Subject | View Object

Appears in Networks:

a(GO:"late endosome") decreases deg(p(MGI:Mapt, var("p.Pro301Leu"))) View Subject | View Object

This process was significantly impaired for tau-P301L and, to higher extent, for tau- A152T (Fig. 2c,d) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

bp(GO:"chaperone-mediated autophagy") increases deg(p(MGI:Mapt, var("p.Pro301Leu"))) View Subject | View Object

Interestingly, although tau-P301L was not degraded in lysosomes, blockage of CMA promoted accumulation of this protein variant, albeit at significantly lower levels than WT and A152T. We propose that overall loss of proteostasis as a consequence of CMA blockage could indirectly affect clearance of tau-P301L through other systems PubMed:29024336

Appears in Networks:
Annotations
MeSH
Lysosomes
Confidence
Medium
MeSH
Brain

bp(GO:"chaperone-mediated autophagy") causesNoChange deg(p(MGI:Mapt, var("p.Pro301Leu"))) View Subject | View Object

The most notable difference between the two tau mutants was the inability of P301L to undergo degradation by CMA or by macroautophagy PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
Medium
MeSH
Brain

bp(GO:macroautophagy) decreases deg(p(MGI:Mapt, var("p.Pro301Leu"))) View Subject | View Object

Macroautophagy blockage resulted in preferential accumulation of A152T, but not WT and P301L tau (Fig. 2e,f) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

bp(GO:macroautophagy) causesNoChange deg(p(MGI:Mapt, var("p.Pro301Leu"))) View Subject | View Object

The most notable difference between the two tau mutants was the inability of P301L to undergo degradation by CMA or by macroautophagy PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
Medium
MeSH
Brain

complex(a(GO:lysosome), p(MGI:Mapt, var("p.Pro301Leu"))) hasComponent p(MGI:Mapt, var("p.Pro301Leu")) View Subject | View Object

Appears in Networks:

complex(a(GO:lysosome), p(MGI:Mapt, var("p.Pro301Leu"))) increases tloc(p(MGI:Mapt, var("p.Pro301Leu")), fromLoc(MESH:"Extracellular Space"), toLoc(GO:lysosome)) View Subject | View Object

Reduced tau-P301L uptake is not caused by a problem in translocation across the lysosomal membrane, but rather by reduced targeting/binding to lysosomes, as we did not detect tau accumulation at the lysosomal membrane PubMed:29024336

Appears in Networks:
Annotations
MeSH
Lysosomes
Confidence
Medium
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) decreases deg(p(MGI:Mapt, var("p.Pro301Leu"))) View Subject | View Object

Contrary to WT tau, which accumulates in e- MI-defective cells, intracellular levels of A152T and P301L tau did not change in cells knocked down for Vps4, suggesting that both point mutations in tau compromise its ability to undergo degradation by this pathway (Fig. 2a,b) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

composite(a(CHEBI:paraquat), p(MGI:Mapt, var("p.Pro301Leu"))) hasComponent p(MGI:Mapt, var("p.Pro301Leu")) View Subject | View Object

Appears in Networks:

composite(a(CHEBI:thapsigargin), p(MGI:Mapt, var("p.Pro301Leu"))) hasComponent p(MGI:Mapt, var("p.Pro301Leu")) View Subject | View Object

Appears in Networks:

path(MESH:"Proteostasis Deficiencies") decreases deg(p(MGI:Mapt, var("p.Pro301Leu"))) View Subject | View Object

Interestingly, although tau-P301L was not degraded in lysosomes, blockage of CMA promoted accumulation of this protein variant, albeit at significantly lower levels than WT and A152T. We propose that overall loss of proteostasis as a consequence of CMA blockage could indirectly affect clearance of tau-P301L through other systems PubMed:29024336

Appears in Networks:
Annotations
MeSH
Lysosomes
Confidence
Medium
MeSH
Brain

bp(MESH:"Cerebrovascular Circulation") association p(MGI:Mapt, var("p.Pro301Leu")) View Subject | View Object

Aberrant cerebral blood flow is a functional defect that occurs in AD and tauNFT mice, and is closely associated with cognitive impairment (Wells et al., 2015) PubMed:30126037

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Out-Edges 33

p(MGI:Mapt, var("p.Pro301Leu")) decreases deg(p(MGI:Mapt)) View Subject | View Object

In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this agerelated disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk-associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Neurons

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Mapt) View Subject | View Object

An increase in overall tau levels has been observed in brains from patients bearing either P301L or A152T mutation on tau (Torres et al., 1998) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) decreases deg(p(MGI:Mapt)) View Subject | View Object

In contrast, the P301L mutation severely impaired lysosomal uptake of tau by CMA, resulting in a sixfold decrease in degradation when compared to WT tau protein (Fig. 1c,d) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Lysosomes
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) decreases deg(p(MGI:Mapt)) View Subject | View Object

Taken together, our in vitro and cell-based studies argue that these two point mutations, A152T and P301L, reduce the normal degradation of tau by CMA, although the P301L mutation has a more pronounced inhibitory effect PubMed:29024336

Appears in Networks:
Annotations
MeSH
Lysosomes
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) decreases deg(p(MGI:Mapt)) View Subject | View Object

In summary, when comparing the pathogenic tau mutation P301L with the risk-associated mutation A152T, we found that both reduced normal turnover of tau by autophagy, but that the effect of the P301L mutation was more pronounced (summarized in Fig. 2g and Fig. S6, Supporting information) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases a(HBP:HBP00006) View Subject | View Object

However, whereas the P301L mutation leads to tau aggregation into paired helical filaments (PHFs) (Barghorn et al., 2000), patients with the risk-associated A152T mutation display higher abundance of oligomers (Coppola et al., 2012) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases a(HBP:HBP00100) View Subject | View Object

However, whereas the P301L mutation leads to tau aggregation into paired helical filaments (PHFs) (Barghorn et al., 2000), patients with the risk-associated A152T mutation display higher abundance of oligomers (Coppola et al., 2012) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) decreases complex(a(GO:lysosome), p(MGI:Mapt)) View Subject | View Object

In contrast, the P301L mutation severely impaired lysosomal uptake of tau by CMA, resulting in a sixfold decrease in degradation when compared to WT tau protein (Fig. 1c,d) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Lysosomes
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) decreases complex(a(GO:lysosome), p(MGI:Mapt)) View Subject | View Object

Reduced tau-P301L uptake is not caused by a problem in translocation across the lysosomal membrane, but rather by reduced targeting/binding to lysosomes, as we did not detect tau accumulation at the lysosomal membrane PubMed:29024336

Appears in Networks:
Annotations
MeSH
Lysosomes
Confidence
Medium
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) decreases bp(GO:"late endosomal microautophagy") View Subject | View Object

Contrary to WT tau, which accumulates in e- MI-defective cells, intracellular levels of A152T and P301L tau did not change in cells knocked down for Vps4, suggesting that both point mutations in tau compromise its ability to undergo degradation by this pathway (Fig. 2a,b) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) decreases deg(p(MGI:Mapt, var("p.Pro301Leu"))) View Subject | View Object

Contrary to WT tau, which accumulates in e- MI-defective cells, intracellular levels of A152T and P301L tau did not change in cells knocked down for Vps4, suggesting that both point mutations in tau compromise its ability to undergo degradation by this pathway (Fig. 2a,b) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases deg(a(MESH:Proteins)) View Subject | View Object

A similar significant increase in protein degradation was observed in response to serum removal in cells expressing either of the mutants (Fig. 3b) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Intracellular Space
Confidence
Low
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases deg(a(MESH:Proteins)) View Subject | View Object

In fact, increased macroautophagy may be responsible for the increase in the degradation of long-lived proteins that we observed for both mutant forms of tau under these conditions (Fig. 3b) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Cells expressing tau-P301L displayed significant upregulation of CMA under basal conditions that was no longer observed upon serum removal (Fig. 3c–e) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Intracellular Space
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases a(GO:autophagosome) View Subject | View Object

We found that abundance of autophagic vacuoles (autophagosomes + autolysosomes) significantly increased in cells expressing either of the two tau mutants (Fig. 4d,e). This increase was mainly due to higher content of autolysosomes (red puncta) (Fig. 4d,e), in support of increased macroautophagic flux PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases a(GO:autolysosome) View Subject | View Object

We found that abundance of autophagic vacuoles (autophagosomes + autolysosomes) significantly increased in cells expressing either of the two tau mutants (Fig. 4d,e). This increase was mainly due to higher content of autolysosomes (red puncta) (Fig. 4d,e), in support of increased macroautophagic flux PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(GO:macroautophagy) View Subject | View Object

We found that abundance of autophagic vacuoles (autophagosomes + autolysosomes) significantly increased in cells expressing either of the two tau mutants (Fig. 4d,e). This increase was mainly due to higher content of autolysosomes (red puncta) (Fig. 4d,e), in support of increased macroautophagic flux PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(GO:macroautophagy) View Subject | View Object

In fact, increased macroautophagy may be responsible for the increase in the degradation of long-lived proteins that we observed for both mutant forms of tau under these conditions (Fig. 3b) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:H2afx) View Subject | View Object

TauNFT mouse brains displayed significantly elevated histone γ-H2ax, a sensitive marker of both double-stranded DNA breaks and cellular senescence (Sedelnikova et al., 2004) (P = 0.0056; Figure 1d-e) PubMed:30126037

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Cdkn1a) View Subject | View Object

TauNFT brains expressed 3-fold higher Cdkn1a than control mice (P = 0.0178, Figure 1f), which was replicated in a separate mouse cohort (P = 0.0086, Figure S1f) PubMed:30126037

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Cdkn2a) View Subject | View Object

Moreover, Cdkn2a was expressed at levels 2.7- and 2.6-fold higher in tauNFT than CTL and tauWT, respectively (P = 0.0303 and P = 0.0352, respectively; Figure 1g); this effect was replicated in an independent mouse cohort (P = 0.0016, Figure S1g) PubMed:30126037

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Il1b) View Subject | View Object

Consistent with the transcriptomic profile in human NFT-bearing neurons and mouse brain tissue (Figure 1a-c), SASP genes were found to be upregulated in tauNFT brains, i.e., Il1b was 4- and 2-fold higher than CTL and tauWT, respectively; and Cxcl1 was 4-fold higher than both control genotypes; Tnfa was 13- and 8-fold higher than CTL and tauWT, respectively; Tlr4 was 3-fold higher than both control genotypes (Figure 2a-d) PubMed:30126037

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Cxcl1) View Subject | View Object

Consistent with the transcriptomic profile in human NFT-bearing neurons and mouse brain tissue (Figure 1a-c), SASP genes were found to be upregulated in tauNFT brains, i.e., Il1b was 4- and 2-fold higher than CTL and tauWT, respectively; and Cxcl1 was 4-fold higher than both control genotypes; Tnfa was 13- and 8-fold higher than CTL and tauWT, respectively; Tlr4 was 3-fold higher than both control genotypes (Figure 2a-d) PubMed:30126037

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Tnf) View Subject | View Object

Consistent with the transcriptomic profile in human NFT-bearing neurons and mouse brain tissue (Figure 1a-c), SASP genes were found to be upregulated in tauNFT brains, i.e., Il1b was 4- and 2-fold higher than CTL and tauWT, respectively; and Cxcl1 was 4-fold higher than both control genotypes; Tnfa was 13- and 8-fold higher than CTL and tauWT, respectively; Tlr4 was 3-fold higher than both control genotypes (Figure 2a-d) PubMed:30126037

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Tlr4) View Subject | View Object

Consistent with the transcriptomic profile in human NFT-bearing neurons and mouse brain tissue (Figure 1a-c), SASP genes were found to be upregulated in tauNFT brains, i.e., Il1b was 4- and 2-fold higher than CTL and tauWT, respectively; and Cxcl1 was 4-fold higher than both control genotypes; Tnfa was 13- and 8-fold higher than CTL and tauWT, respectively; Tlr4 was 3-fold higher than both control genotypes (Figure 2a-d) PubMed:30126037

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(GO:"NIK/NF-kappaB signaling") View Subject | View Object

Consistent with NFkB pathway activation and the SASP profile, nuclear localized NFkB p65 was significantly increased in tauNFT brains (Figure 2e-f) PubMed:30126037

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Rela) View Subject | View Object

Consistent with NFkB pathway activation and the SASP profile, nuclear localized NFkB p65 was significantly increased in tauNFT brains (Figure 2e-f) PubMed:30126037

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Glb1) View Subject | View Object

Examination of the gene that codes for the hydrolase enzyme, galactosidase beta 1 (Glb1), revealed that tauNFT mice expressed higher Glb1 gene expression than controls (Figure S3) PubMed:30126037

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases path(MESH:Tauopathies) View Subject | View Object

TauNFT mice develop aggressive tauopathy with NFT formation in early life, and show a senescence-associated transcriptomic profile with NFT onset (Figure 1c) PubMed:30126037

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases a(GO:"neurofibrillary tangle") View Subject | View Object

TauNFT mice develop aggressive tauopathy with NFT formation in early life, and show a senescence-associated transcriptomic profile with NFT onset (Figure 1c) PubMed:30126037

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(GO:"cellular senescence") View Subject | View Object

TauNFT mice develop aggressive tauopathy with NFT formation in early life, and show a senescence-associated transcriptomic profile with NFT onset (Figure 1c) PubMed:30126037

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) association bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Aberrant cerebral blood flow is a functional defect that occurs in AD and tauNFT mice, and is closely associated with cognitive impairment (Wells et al., 2015) PubMed:30126037

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

In brain tissue with tau pathology, cerebral blood flow was elevated in tauNFT Mapt0/0 vehicle-treated mice (21% whole brain, P = 0.045; cortex, 48.7%, P = 0.051, Figure S5d, e), and consistent with previous reports of tauNFT mice on a Mapt+/+ background (Wells et al., 2015) PubMed:30126037

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Tauopathies

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

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.