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p(MGI:Mapt, var("p.Ala152Thr"))

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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 1

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

In-Edges 10

p(MGI:Mapt) hasVariant p(MGI:Mapt, var("p.Ala152Thr")) View Subject | View Object

Appears in Networks:

composite(a(CHEBI:paraquat), p(MGI:Mapt, var("p.Ala152Thr"))) hasComponent p(MGI:Mapt, var("p.Ala152Thr")) View Subject | View Object

Appears in Networks:

a(GO:"late endosome") decreases deg(p(MGI:Mapt, var("p.Ala152Thr"))) 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.Ala152Thr"))) View Subject | View Object

Tau-A152T displayed very similar degradation dynamics, although this mutation slightly reduced tau’s rates of lysosomal degradation (20% inhibition) when compared with WT tau (Fig. 1a,b). PubMed:29024336

Appears in Networks:
Annotations
MeSH
Lysosomes
Confidence
High
MeSH
Brain

bp(GO:"chaperone-mediated autophagy") increases deg(p(MGI:Mapt, var("p.Ala152Thr"))) View Subject | View Object

Blockage of CMA in cells expressing tau-A152T also resulted in significant accumulation of this variant and ablated its lysosomal degradation, suggesting preferential degradation of A152T by CMA (Fig. 1a,b) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Lysosomes
Confidence
High
MeSH
Brain

bp(GO:"chaperone-mediated autophagy") increases deg(p(MGI:Mapt, var("p.Ala152Thr"))) View Subject | View Object

In the case of tau-A152T, the dynamics of internalization/degradation through CMA were comparable to WT tau (Fig. 1c,d), in agreement with our studies in intact cells in culture (Fig. 1a, b), but we found a significantly higher amount of tau-A152T bound to the membrane of CMA-active lysosomes (Fig. 1c,d) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Lysosomes
Confidence
Medium
MeSH
Brain

bp(GO:macroautophagy) increases deg(p(MGI:Mapt, var("p.Ala152Thr"))) 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

complex(a(GO:lysosome), p(MGI:Mapt, var("p.Ala152Thr"))) hasComponent p(MGI:Mapt, var("p.Ala152Thr")) View Subject | View Object

Appears in Networks:

p(MGI:Mapt, var("p.Ala152Thr")) decreases deg(p(MGI:Mapt, var("p.Ala152Thr"))) 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:thapsigargin), p(MGI:Mapt, var("p.Ala152Thr"))) hasComponent p(MGI:Mapt, var("p.Ala152Thr")) View Subject | View Object

Appears in Networks:

Out-Edges 16

p(MGI:Mapt, var("p.Ala152Thr")) 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.Ala152Thr")) 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.Ala152Thr")) 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.Ala152Thr")) 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.Ala152Thr")) increases a(HBP:HBP00009) 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.Ala152Thr")) 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.Ala152Thr")) decreases bp(GO:"late endosomal microautophagy") View Subject | View Object

In the presence of any of the tau proteins, we found some sequestration of the probe in the multivesicular bodies, albeit significantly less in cells expressing the WT and A152T protein PubMed:29024336

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

p(MGI:Mapt, var("p.Ala152Thr")) decreases deg(p(MGI:Mapt, var("p.Ala152Thr"))) 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.Ala152Thr")) increases deg(a(MESH:Proteins)) View Subject | View Object

Cells expressing tau-A152T displayed significantly higher rates of intracellular protein degradation than the other cells under basal conditions (Fig. 3a) PubMed:29024336

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

p(MGI:Mapt, var("p.Ala152Thr")) 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.Ala152Thr")) 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.Ala152Thr")) increases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

We did however find that under serum deprivation conditions, tau-A152T-expressing cells displayed significantly higher CMA (Fig. 3d,e; 30% increase) than control cells PubMed:29024336

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

p(MGI:Mapt, var("p.Ala152Thr")) 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.Ala152Thr")) 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.Ala152Thr")) 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.Ala152Thr")) 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

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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.