1. Catalog
  2. Citations
  3. PubMed:29121589

PubMed: 29121589

Title
Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.
Journal
Redox biology
Volume
14
Issue
None
Pages
522-534
Date
2018-04-01
Authors
Cuadrado A | Kügler S | Lastres-Becker I

Evidence 840593c52a
JSON

Wild-type MEFs treated with DMF (20 μM) showed a time-dependent response effect activating phosphorylation of ERK (Fig. 2A, B) and p38 (Fig. 2A, C), that was maximal within 5 min. The Ser/Thr protein kinase AKT, an upstream regulator of GSK-3β, was also activated after 5 min as determined by increased phosphorylation of S473 (Fig. 2A, D)

a(CHEBI:"dimethyl fumarate") increases act(p(FPLX:ERK)) View Subject | View Object

Appears in Networks:

a(CHEBI:"dimethyl fumarate") increases act(p(FPLX:p38)) View Subject | View Object

Appears in Networks:

a(CHEBI:"dimethyl fumarate") positiveCorrelation p(FPLX:AKT, pmod(Ph, Ser, 473)) View Subject | View Object

Appears in Networks:

p(FPLX:AKT, pmod(Ph, Ser, 473)) positiveCorrelation a(CHEBI:"dimethyl fumarate") View Subject | View Object

Appears in Networks:

p(FPLX:AKT, pmod(Ph, Ser, 473)) increases act(p(FPLX:AKT)) View Subject | View Object

Appears in Networks:

Evidence 654e89c26d
JSON

DMF increased the phosphorylation levels of GSK-3βSer9 in both genotypes, indicating that this effect is upstream of NRF2 as shown in Fig. 3A.

a(CHEBI:"dimethyl fumarate") increases p(HGNC:GSK3B, pmod(Ph, Ser, 9)) View Subject | View Object

Appears in Networks:
Annotations
Uberon
hippocampal formation

Evidence d11b4017bd
JSON

Taken together, our results show that DMF reduces GSK-3 activity in vivo as determined by a significant and subtle reduction in the phosphorylation levels of its two substrates TAU and CRMP2 respectively.

a(CHEBI:"dimethyl fumarate") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

a(CHEBI:"dimethyl fumarate") negativeCorrelation p(HGNC:DPYSL2, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:DPYSL2, pmod(Ph)) negativeCorrelation a(CHEBI:"dimethyl fumarate") View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B), ma(kin)) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B), ma(kin)) directlyIncreases p(HGNC:DPYSL2, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence 11be4dff2a
JSON

Astrocytes displayed enlarged bodies and ramifications (Type B morphology), consistent with a reactive state after TAUP301L expression in Nrf2+/+ and Nrf2−/− mice (Fig. 6A left panels). However, only astrocytes from Nrf2+/+ mice treated with DMF were maintained in a resting morphology (Type A) (Fig. 6A right panels). Concerning microglia, TAUP301L expression induced a very significant increase in IBA1+ microglia at the ipsilateral hippocampal side of Nrf2+/+ and Nrf2−/− mice (Fig. 7A), which was confirmed by stereological quantification (Fig. 7B). DMF treatment reduced significantly this microgliosis in Nrf2+/+ but not in Nrf2−/− mice, reinforcing the idea of NRF2-dependent anti-inflammatory effect

a(CHEBI:"dimethyl fumarate") decreases a(HBP:Astrogliosis) View Subject | View Object

Appears in Networks:

a(CHEBI:"dimethyl fumarate") decreases a(HBP:Microgliosis) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Leu")) increases a(HBP:Astrogliosis) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Leu")) increases a(HBP:Microgliosis) View Subject | View Object

Appears in Networks:

Evidence eb6772c96e
JSON

Messenger RNA analysis of two pro-inflammatory markers such as IL-1β and inducible nitric oxide synthase (iNOS) indicate that TAUP301L expression induce Il-1β (Fig. 6D) and iNOS (Fig. 7D) mRNA expression in both genotypes and DMF treatment decreased this expression only in Nrf2+/+ mice.

a(CHEBI:"dimethyl fumarate") decreases r(MGI:Il1b) View Subject | View Object

Appears in Networks:

a(CHEBI:"dimethyl fumarate") decreases r(MGI:Nos2) View Subject | View Object

Appears in Networks:

a(CHEBI:"dimethyl fumarate") decreases bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Leu")) increases r(MGI:Nos2) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

r(MGI:Il1b) biomarkerFor bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:

r(MGI:Nos2) biomarkerFor bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:

Evidence 1d1b0d3cc5
JSON

The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10].

complex(p(HGNC:BTRC), p(HGNC:CUL1), p(HGNC:NFE2L2, pmod(Ph))) increases p(HGNC:NFE2L2, pmod(UbPoly)) View Subject | View Object

Appears in Networks:

p(HGNC:BTRC) increases complex(p(HGNC:BTRC), p(HGNC:CUL1), p(HGNC:NFE2L2, pmod(Ph))) View Subject | View Object

Appears in Networks:

p(HGNC:NFE2L2) positiveCorrelation p(FPLX:AKT) View Subject | View Object

Appears in Networks:

p(FPLX:AKT) increases p(HGNC:GSK3B, pmod(Ph, Ser, 9)) View Subject | View Object

Appears in Networks:

p(FPLX:AKT) positiveCorrelation p(HGNC:NFE2L2) View Subject | View Object

Appears in Networks:

p(HGNC:GSK3B) decreases p(HGNC:NFE2L2) View Subject | View Object

Appears in Networks:

p(HGNC:GSK3B) increases p(HGNC:NFE2L2, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:GSK3B, pmod(Ph, Ser, 9)) decreases act(p(HGNC:GSK3B), ma(kin)) View Subject | View Object

Appears in Networks:

Evidence a5ed14a8a5
JSON

NRF2 is regulated principally by two different mechanisms. The best established mechanism is the control of protein stability by Kelch-like ECH-associated protein 1 (KEAP1). KEAP1 is an ubiquitin E3 ligase substrate adapter for a Cullin3/Rbx1-dependent E3 ubiquitin ligase complex; henceforth binding of KEAP1 to NRF2 mediates ubiquitination and subsequent proteasomal degradation of NRF2 [7].

complex(p(HGNC:CUL3), p(HGNC:KEAP1), p(HGNC:NFE2L2)) increases p(HGNC:NFE2L2, pmod(UbPoly)) View Subject | View Object

Appears in Networks:

p(HGNC:KEAP1) increases complex(p(HGNC:CUL3), p(HGNC:KEAP1), p(HGNC:NFE2L2)) View Subject | View Object

Appears in Networks:

p(HGNC:NFE2L2, pmod(UbPoly)) increases deg(p(HGNC:NFE2L2)) View Subject | View Object

Appears in Networks:

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.