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PubMed: 27594586

Title
MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations.
Journal
Stem cell reports
Volume
7
Issue
None
Pages
316-324
Date
2016-09-13
Authors
Karydas A | Futai K | Lopez-Gonzalez R | Miller BL | Mao W | Biswas MHU | Almeida S | Gao FB | Geschwind MD | Zhang Z | Biernat J | Mandelkow EM

Evidence c5ad644c6e
JSON

ERK phosphorylation in MAPT mutant neurons was blocked by treatment with PD98059, a specific inhibitor of MEK-mediated activation of ERK (Li et al., 2001) (Figures 4B and 4C)

a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") decreases p(FPLX:ERK, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 368b73c15b
JSON

Correspondingly, the level and activity of secreted MMP-9 was greatly suppressed in both tau-A152T and MAPT IVS10+16 patient neurons (Figures 4B and 4C), suggesting that MMP-9 expression is regulated by the ERK signaling pathway in cortical neurons

a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") decreases sec(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") decreases act(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

bp(GO:"ERK1 and ERK2 cascade") regulates p(HGNC:MMP9) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence c71bf60195
JSON

Interestingly, the level and activity of MMP-2 was not affected after the PD98059 treatment in tau-A152T neurons (Figure 4B) and MAPT IVS10+16 neurons (Figure 4C)

a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") causesNoChange act(p(HGNC:MMP2)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") causesNoChange p(HGNC:MMP2) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence c793ba0246
JSON

We treated these neurons with staurosporine, a broad-spectrum kinase inhibitor that induces apoptosis (Budd et al., 2000); rotenone, a complex inhibitor that induces mitochondrial dysfunction (Sherer et al., 2003); and rapamycin, an inhibitor of the mammalian target of the rapamycin (mTOR) signaling pathway with many downstream effects (Li et al., 2014)

a(CHEBI:rotenone) increases bp(HBP:HBP00037) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

a(CHEBI:sirolimus) decreases bp(GO:"TOR signaling") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

a(CHEBI:staurosporine) increases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence db72c96425
JSON

MMP-9/MMP-2 mRNA levels in tau-A152T and MAPT IVS10+16 neurons were significantly higher than that in control neurons (Figure S2J), and rapamycin increased these levels (p < 0.01) (Figure 3C)

a(CHEBI:sirolimus) increases r(HGNC:MMP9) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

a(CHEBI:sirolimus) increases r(HGNC:MMP2) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) increases r(HGNC:MMP9) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) increases r(HGNC:MMP2) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) increases r(HGNC:MMP9) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) increases r(HGNC:MMP2) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 851d6f66c8
JSON

When measuring cell viability using the MTT assay, we found that patient-specific neurons are more sensitive than control neurons to cell death induced by rapamycin (Figure 3B) but not by staurosporine or rotenone (Figures S3B and S3C), suggesting compromised function in the mTOR pathway or related molecular pathways

composite(a(CHEBI:rotenone), p(HGNC:MAPT, var("p.Ala152Thr"))) causesNoChange bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

composite(a(CHEBI:sirolimus), p(HGNC:MAPT, var("p.Ala152Thr"))) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

composite(a(CHEBI:staurosporine), p(HGNC:MAPT, var("p.Ala152Thr"))) causesNoChange bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence b73844fc4f
JSON

Four weeks after terminal differentiation, 80% of cells were positive for the neuron-specific marker MAP2, and there was no significant difference between control and patient neurons (Figure S2A)

p(HGNC:MAPT, var("p.Ala152Thr")) increases p(HGNC:MAP2) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) increases p(HGNC:MAP2) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 5d39c34f14
JSON

The percentages of VGLUT1-positive excitatory and GABA-positive inhibitory neurons were similar in neuronal cultures differentiated from control and patient iPSCs (Figures S2B and S2C)

p(HGNC:MAPT, var("p.Ala152Thr")) causesNoChange a(GO:"symmetric, GABA-ergic, inhibitory synapse") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) causesNoChange p(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) causesNoChange a(GO:"symmetric, GABA-ergic, inhibitory synapse") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) causesNoChange p(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 285cf3f279
JSON

Moreover, the total expression levels of tau and PSD-95 were the same in 1-month-old neurons derived from control and patient iPSCs (Figure 1B)

p(HGNC:MAPT, var("p.Ala152Thr")) causesNoChange p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) causesNoChange p(HGNC:DLGAP4) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) causesNoChange p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) causesNoChange p(HGNC:DLGAP4) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence c1b66358a1
JSON

The resting membrane potential did not differ among neurons differentiated from all iPSC lines (Figure S2D)

p(HGNC:MAPT, var("p.Ala152Thr")) causesNoChange bp(MESH:"Membrane Potentials") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) causesNoChange bp(MESH:"Membrane Potentials") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 8ebb0ac36f
JSON

Thus, both molecular and electrophysiological analyses suggest MAPT mutations do not affect early neuronal differentiation

p(HGNC:MAPT, var("p.Ala152Thr")) causesNoChange bp(GO:"neuron differentiation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) causesNoChange bp(GO:"neuron differentiation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence e96d8f5473
JSON

Tau-A152T neurons had >10-fold higher level and activity of secreted MMP-9 than control neurons (Figures 2A and 2B), as did MAPT IVS10+16 neurons to a lesser extent (Figures 2C and 2D)

p(HGNC:MAPT, var("p.Ala152Thr")) increases act(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) increases sec(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) increases act(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) increases sec(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 7e13deb6c0
JSON

The level of secreted MMP-9 and MMP-2 was also increased in cortical neurons derived from a published iPSC line with the tau-A152T mutation (Fong et al., 2013) (Figures 2E and 2F)

p(HGNC:MAPT, var("p.Ala152Thr")) increases sec(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) increases sec(p(HGNC:MMP2)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence f4ac108ff7
JSON

It is worth noting that the level and activity of secreted MMP-9 in tau- A152T neurons is also substantially higher than that in MAPT IVS10+16 neurons (Figure 2)

p(HGNC:MAPT, var("p.Ala152Thr")) increases act(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) increases sec(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) increases act(p(HGNC:MMP2)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) increases sec(p(HGNC:MMP2)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence b70b83a701
JSON

This increase is likely in part due to transcriptional regulation, since the mRNA levels of MMP-9 and MMP-2 in tau-A152T and MAPT IVS10+16 neurons were higher than in control neurons (Figure S2J)

p(HGNC:MAPT, var("p.Ala152Thr")) increases r(HGNC:MMP9) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) increases r(HGNC:MMP2) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) increases r(HGNC:MMP9) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) increases r(HGNC:MMP2) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 9e83c30177
JSON

We found that, indeed, TUJ1+ neurons showed reduced survival as measured by TUNEL analysis (Figure 3A)

p(HGNC:MAPT, var("p.Ala152Thr")) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 3d24568e7b
JSON

The level of phosphorylated ERK (p-ERK) was significantly increased in tau-A152T neurons and to a lesser extent in MAPT IVS10+16 patient neurons (Figure 4A)

p(HGNC:MAPT, var("p.Ala152Thr")) increases p(FPLX:ERK, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 204b51d746
JSON

Interestingly, this ratio is also increased, but to a lesser extent, in tau-A152T neurons (Figure S3F)

p(HGNC:MAPT, var("p.Ala152Thr")) increases a(HBP:HBP00045) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MAPT, var("p.Ala152Thr")) decreases a(HBP:HBP00044) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence a573b45019
JSON

As expected, the 4R/3R tau ratio is greatly increased in MAPT IVS10+16 neurons (Figure S3F) but not in GRN mutant neurons (Figure S3G)

g(DBSNP:rs63751011) increases a(HBP:HBP00045) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

g(DBSNP:rs63751011) decreases a(HBP:HBP00044) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 493a258a08
JSON

It is known that MMP-9 expression is regulated by ERK (Wang et al., 2006)

p(FPLX:ERK) regulates p(HGNC:MMP9) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence a3052f89cb
JSON

We found the level and activity of secreted MMP-9 to correlate well with the extent of ERK phosphorylation (Figure S4A)

p(FPLX:ERK, pmod(Ph)) positiveCorrelation act(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(FPLX:ERK, pmod(Ph)) positiveCorrelation sec(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

act(p(HGNC:MMP9)) positiveCorrelation p(FPLX:ERK, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

sec(p(HGNC:MMP9)) positiveCorrelation p(FPLX:ERK, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence b6812f0664
JSON

Interestingly, the level and activity of secreted MMP-9 in HEK293 cells expressing WT 3R tau and 3R tau-A152T are similar (Figures S4B and S4C)

p(HBP:HBP00044, var("p.Ala152Thr")) causesNoChange sec(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
High
MeSH
Frontotemporal Dementia

p(HBP:HBP00044, var("p.Ala152Thr")) causesNoChange act(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
High
MeSH
Frontotemporal Dementia

Evidence c0b14909b1
JSON

ERK phosphorylation is also not affected by A152T mutation in 3R tau (Figure S4D)

p(HBP:HBP00044, var("p.Ala152Thr")) causesNoChange p(FPLX:ERK, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
Medium
MeSH
Frontotemporal Dementia

Evidence a7e0e27798
JSON

However, the secreted MMP-9 level and activity in conditioned medium was significantly higher in cultures of cells expressing tau-A152T than WT tau (Figure 4E)

p(HBP:HBP00045, var("p.Ala152Thr")) increases sec(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
High
MeSH
Frontotemporal Dementia

p(HBP:HBP00045, var("p.Ala152Thr")) increases act(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
High
MeSH
Frontotemporal Dementia

Evidence 95d3a27b5b
JSON

Taken together, these findings strongly suggest that 4R tau-A152T activates the ERK pathway more strongly, which in turn increases the level and activity of secreted MMP-9. 4R tau-A152T expression (Figures 4E and 4F) but not inhibition of ERK activity (Figures 4B and 4C) also increases the total activity of secreted MMP-2, suggesting that tau-A152T increases the level and activity of secreted MMP-2, likely through an ERK-independent pathway

p(HBP:HBP00045, var("p.Ala152Thr")) increases sec(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
High
MeSH
Frontotemporal Dementia

p(HBP:HBP00045, var("p.Ala152Thr")) increases act(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
High
MeSH
Frontotemporal Dementia

p(HBP:HBP00045, var("p.Ala152Thr")) increases bp(GO:"ERK1 and ERK2 cascade") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
High
MeSH
Frontotemporal Dementia

p(HBP:HBP00045, var("p.Ala152Thr")) increases sec(p(HGNC:MMP2)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
High
MeSH
Frontotemporal Dementia

p(HBP:HBP00045, var("p.Ala152Thr")) increases act(p(HGNC:MMP2)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
High
MeSH
Frontotemporal Dementia

Evidence 5a355741ce
JSON

The MMP-9 mRNA level was also higher in cells expressing tau-A152T (Figure 4F)

p(HBP:HBP00045, var("p.Ala152Thr")) increases r(HGNC:MMP9) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
High
MeSH
Frontotemporal Dementia

Evidence 5f63702704
JSON

Correspondingly, the level of p-ERK was also elevated in HEK293 cells expressing tau-A152T (Figure 4E)

p(HBP:HBP00045, var("p.Ala152Thr")) increases p(FPLX:ERK, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
Confidence
Medium
MeSH
Frontotemporal Dementia

Evidence 4ab634b851
JSON

To examine the contributions of increased MMP-9 and MMP-2 to neuronal cell death, we used two compounds that are known to inhibit MMP-9 and MMP-2 activity (catalog #444278 and #444244, Calbiochem). We found that this treatment partially rescued the increased sensitivity to rapamycin and improved survival (Figure 3B)

act(p(HGNC:MMP2)) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

act(p(HGNC:MMP9)) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence e83e3d2797
JSON

MMP-2 and MMP-9 seem to induce cell death directly, since this treatment also increased the TUNEL signal in iPSC-derived neurons (Figures S3D and S3E)

p(HGNC:MMP2) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

p(HGNC:MMP9) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Cerebral Cortex
MeSH
Neurons
MeSH
Frontotemporal Dementia

Evidence 6054f27e78
JSON

MMP-9 directly cleaves Huntingtin protein in Huntington’s disease, a progressive neurodegenerative disorder (Miller et al., 2010)

p(HGNC:MMP9) increases p(HGNC:HTT, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Huntington Disease

Evidence 23f1cf8c8e
JSON

Moreover, dysregulation of MMP-9 in the CNS is a cause of neuronal developmental disorders (Reinhard et al., 2015)

act(p(HGNC:MMP9)) association path(MESH:"Neurodevelopmental Disorders") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Central Nervous System

path(MESH:"Neurodevelopmental Disorders") association act(p(HGNC:MMP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Central Nervous System

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.