The NRF2 transcriptional target, OSGIN1, contributes to monomethyl fumarate-mediated cytoprotection in human astrocytes.
Dimethyl fumarate (DMF) is indicated for the treatment of relapsing multiple sclerosis and may exert therapeutic effects via activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway. Following oral DMF administration, central nervous system (CNS) tissue is predominantly exposed to monomethyl fumarate (MMF), the bioactive metabolite of DMF, which can stabilize NRF2 and induce antioxidant gene expression; however, the detailed NRF2-dependent mechanisms modulated by MMF that lead to cytoprotection are unknown. Our data identify a mechanism for MMF-mediated cytoprotection in human astrocytes that functions in an OSGIN1-dependent manner, specifically via upregulation of the OSGIN1-61 kDa isoform. NRF2-dependent OSGIN1 expression induced P53 nuclear translocation following MMF administration, leading to cell-cycle inhibition and cell protection against oxidative challenge. This study provides mechanistic insight into MMF-mediated cytoprotection via NRF2, OSGIN1, and P53 in human CNS-derived cells and contributes to our understanding of how DMF may act clinically to ameliorate pathological processes in neurodegenerative disease.
Neurology Research, Biogen Inc., Cambridge, MA, 02142, USA.|Boston University School of Medicine, Boston, MA 02118, USA.
Melanie S
MS
Brennan
Neurology Research, Biogen Inc., Cambridge, MA, 02142, USA.
Maria F
MF
Matos
Neurology Research, Biogen Inc., Cambridge, MA, 02142, USA.
Karl E
KE
Richter
Neurology Research, Biogen Inc., Cambridge, MA, 02142, USA.
Bing
B
Li
Neurology Research, Biogen Inc., Cambridge, MA, 02142, USA.
Robert H
RH
Scannevin
D051017:Apoptosis Regulatory Proteins; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D019610:Cytoprotection; D005650:Fumarates / Q000378:metabolism*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D005650:Fumarates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C432368:OSGIN1 protein, human; D011506:Proteins