Neurology Research, Biogen Inc., Cambridge, MA, 02142, USA.
Boston University School of Medicine, Boston, MA 02118, USA.
Sci Rep. 2017 Feb 9;7:42054. doi: 10.1038/srep42054.
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.
富马酸二甲酯（DMF）用于治疗复发型多发性硬化症，其可能通过激活核因子（红系衍生 2）样 2（NRF2）通路发挥治疗作用。在口服 DMF 后，中枢神经系统（CNS）组织主要暴露于 DMF 的生物活性代谢物单甲基富马酸（MMF）中，MMF 可以稳定 NRF2 并诱导抗氧化基因表达；然而，导致细胞保护的 MMF 调节的详细的 NRF2 依赖性机制尚不清楚。我们的数据确定了 MMF 介导的人星形胶质细胞中细胞保护的一种机制，该机制以 OSGIN1 依赖性方式起作用，具体是通过上调 OSGIN1-61 kDa 同工型。MMF 给药后，NRF2 依赖性 OSGIN1 表达诱导 P53 核易位，导致细胞周期抑制和细胞免受氧化应激的保护。这项研究为 MMF 通过 NRF2、OSGIN1 和 P53 介导的人中枢神经系统来源细胞中的细胞保护提供了机制见解，并有助于我们理解 DMF 如何在临床上发挥作用，改善神经退行性疾病中的病理过程。
