PXD008314

PXD008314 is an original dataset announced via ProteomeXchange.

Title	Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveal Actions Independent of Keap1 Activation
Description	The fumarate ester dimethyl fumarate (DMF) has been introduced recently for the treatment of relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory condition resulting in neuronal demyelination and axonal loss. The complete mechanism of DMF action is unknown, but involves the depletion of intracellular glutathione and modification of thiols on Kelch-like ECH-associated protein 1 (Keap1), which in turn induces the expression of antioxidant response element genes. Previous work by our laboratory has shown that DMF reacts with a wide range of protein thiols in adipocytes, detected following ester hydrolysis by an antibody recognizing succinated proteins. We proposed that other intracellular thiol residues may also be irreversibly modified by DMF in neurons and astrocytes. DMF treatment of primary rodent neurons and astrocytes, as well as differentiated N1E-115 cells, resulted in the modification of 24 novel target proteins by mass spectrometry. Using this approach, we confirmed the identification and site of modification of the identified proteins, which include cofilin-1, tubulin and collapsin response mediator protein 2 (CRMP2). An in vitro functional assay that measures the ability of cofilin-1 to sever the actin cytoskeleton demonstrated that DMF-modified cofilin-1 loses activity and generates less monomeric actin, potentially inhibiting cofilin’s cytoskeletal remodeling activity; an effect that could be beneficial in the modulation of myelination during RRMS. DMF modification of tubulin did not significantly impact axonal lysosomal trafficking. The oxygen consumption rate of N1E-115 neurons and the levels of proteins related to mitochondrial energy production were only slightly affected by the highest doses of DMF, confirming that DMF treatment does not impair cellular respiratory function. In summary, we demonstrate that in addition to the stimulation of the antioxidant response, DMF resulted in electrophilic modification of novel protein targets that provide new insight on the mechanisms supporting the neuroprotective and re-myelination benefits associated with DMF treatment.
HostingRepository	PRIDE
AnnounceDate	2019-02-19
AnnouncementXML	Submission_2019-02-19_00:29:58.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Norma Frizzell
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	S-pyridylethyl-L-cysteine; monohydroxylated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2017-11-28 08:02:02	ID requested
⏵ 1	2019-02-19 00:29:59	announced

Piroli GG, Manuel AM, Patel T, Walla MD, Shi L, Lanci SA, Wang J, Galloway A, Ortinski PI, Smith DS, Frizzell N, Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveals Actions Independent of Nrf2 Stabilization. Mol Cell Proteomics, 18(3):504-519(2019) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: Neurons, astrocytes, dimethyl fumarate, chemical modification

Norma Frizzell
contact affiliation	Department of Pharmacology, Physiology & Neuroscience School of Medicine University of South Carolina Columbia, South Carolina, 29209 USA
contact email	norma.frizzell@uscmed.sc.edu
lab head
Norma Frizzell
contact affiliation	University of South CAROLINA
contact email	norma.frizzell@uscmed.sc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD008314
     1. Label: PRIDE project
     2. Name: Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveal Actions Independent of Keap1 Activation