2019
DOI: 10.1074/mcp.ra118.000922
|View full text |Cite
|
Sign up to set email alerts
|

Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveals Actions Independent of Nrf2 Stabilization

Abstract: In BriefDimethyl fumarate (DMF) is a reactive fumarate ester used in the treatment of relapsing remitting multiple sclerosis; however, the neuroprotective mechanisms of DMF action are incompletely understood. The results uncover novel DMF-modified cysteine residues in neurons and astrocytes, including cytoskeletal proteins whose modulation by DMF may alter the response to neurodegenerative cues and myelination. Graphical Abstract Highlights• Dimethyl fumarate covalently modifies cysteine residues in neurons an… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
1
1
1
1

Citation Types

2
27
0

Year Published

2019
2019
2022
2022

Publication Types

Select...
5
1
1

Relationship

1
6

Authors

Journals

citations
Cited by 37 publications
(30 citation statements)
references
References 60 publications
2
27
0
Order By: Relevance
“…39 Using mass spectrometry, Piroli et al recently identified 24 novel DMFmodified proteins in neurons and astrocytes, including cofilin-1, tubulin and collapsing response mediator protein 2 (CRMP2). 40 Using human plasmacytoid DCs, an important cell type in systemic lupus erythematosus (SLE), as well as in psoriasis and MS, Zaro et al recently described anti-inflammatory effects of DMF that are dependent on cysteine-13 of IRAK4, 41 a key enzyme in IL-1, IL-18 and Toll-like receptor (TLR) signaling. Covalent modification at this site by DMF prevents the assembly of IRAK4 and the adapter protein MyD88, leading to a reduced production of cytokines and chemokines including IFN-α and TNFα, thereby identifying cysteine 13 on IRAK4 as a vital regulatory point for adequate innate immune responses and potentially a novel therapeutic target for suppressing an overactive immune system.…”
Section: Drugs With Anti-inflammatory Properties That Target Metabolimentioning
confidence: 99%
“…39 Using mass spectrometry, Piroli et al recently identified 24 novel DMFmodified proteins in neurons and astrocytes, including cofilin-1, tubulin and collapsing response mediator protein 2 (CRMP2). 40 Using human plasmacytoid DCs, an important cell type in systemic lupus erythematosus (SLE), as well as in psoriasis and MS, Zaro et al recently described anti-inflammatory effects of DMF that are dependent on cysteine-13 of IRAK4, 41 a key enzyme in IL-1, IL-18 and Toll-like receptor (TLR) signaling. Covalent modification at this site by DMF prevents the assembly of IRAK4 and the adapter protein MyD88, leading to a reduced production of cytokines and chemokines including IFN-α and TNFα, thereby identifying cysteine 13 on IRAK4 as a vital regulatory point for adequate innate immune responses and potentially a novel therapeutic target for suppressing an overactive immune system.…”
Section: Drugs With Anti-inflammatory Properties That Target Metabolimentioning
confidence: 99%
“…We then measured KGDHC activity in both the BS and OB of WT and Ndufs4 KO mice, and found that in both brain regions it was significantly lower in the KO mice (24.2 and 31.2% decrease in BS and OB, p<0.05 and 0.01 respectively, Figures 2B and 2C). Fumarate mediated reduction in the activity of the dehydrogenase was also confirmed in vitro following incubation of an isolated KGDHC standard with a range of dimethyl fumarate (DMF) concentrations, as treatment with this reactive fumarate ester also results in protein succination (Piroli et al, 2019). Figure 2D demonstrates that DMF treatment caused a dose-dependent decrease in the activity of the complex.…”
Section: Succination Reduces the Activity Of The α-Ketoglutarate Dehymentioning
confidence: 67%
“…N1E-115 cells neuroblastoma cells (subclone N1E-115-1) were expanded in non-differentiation medium containing 90% DMEM and 10% FBS, as previously described (Piroli et al, 2016;Piroli et al, 2019). At 80% confluence, the cells were differentiated into neurons in the presence of 2% FBS and 1.25% dimethyl sulfoxide in DMEM for 5 days.…”
Section: N1e-115 Cellsmentioning
confidence: 99%
See 2 more Smart Citations