Year-end Sale % OFF 
Abstract
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.
Highlights
In vivo mouse transcriptional studies uncovered diverse tissue-dependent NRF2 target genes following dimethyl fumarate (DMF) treatment, in the CNS, including oxidative stress induced growth inhibitor 1 (OSGIN1), known as ovary, kidney and liver protein 38 (OKL38) or bone marrow stromal cell-derived growth inhibitor (BDGI)[17]
In contrast to studies using tumor cells, we identify a novel mechanism by which OSGIN1 mediates astrocyte protection against hydrogen peroxide (H2O2)-induced oxidative injury via induction and nuclear translocation of protein 53 (P53)
Human astrocytes were chosen for in vitro investigation of OSGIN1 regulation because the NRF2 pathway is relatively dormant in adult neurons but strongly modulated in astrocytes[23,24], and astrocyte overexpression of NRF2 confers protection to neurons in astrocyte-neuronal co-cultures[25]
Summary
In vivo mouse transcriptional studies uncovered diverse tissue-dependent NRF2 target genes following DMF treatment, in the CNS, including oxidative stress induced growth inhibitor 1 (OSGIN1), known as ovary, kidney and liver protein 38 (OKL38) or bone marrow stromal cell-derived growth inhibitor (BDGI)[17]. One study identified OSGIN1 as an NRF2 transcriptional target[18], the majority of OSGIN1 research describes this gene under the transcriptional control of tumor suppressor protein 53 (P53) in mediating cell growth, differentiation and death[19,20]. These studies used tumor cells and suggested alternative splicing of OSGIN1 contributed to its function[21]. It is unknown whether OSGIN1 and its isoforms are differentially regulated across cell types or if transcription factors differentially regulate OSGIN1 isoforms. We show that OSGIN1 cooperates with NRF2 and P53 to protect astrocytes against oxidative insult in the presence of MMF
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
