The Nrf2 transcriptional target, OSGIN1, contributes to the cytoprotective properties of dimethyl fumarate
Brennan, Melanie Shackett
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Understanding how defense signaling pathways regulate neuronal protection in the compromised central nervous system (CNS) is essential for combating neurodegenerative disorders. This is apparent in the intrinsic activation of the transcription factor Nrf2 during periods of oxidative stress, a hallmark of neurodegeneration. This regulator of the antioxidant response induces the transcription of genes essential for protecting against oxidative stress-induced damage and is a prime target for drug discovery. Delayed-release dimethyl fumarate (DMF), currently approved for the treatment of relapsing-remitting forms of multiple sclerosis (MS), is believed to mediate its effect via the Nrf2 pathway; however, the exact mechanisms of action are unknown. The primary aim of the studies outlined in this dissertation was to identify the molecular mechanisms of Nrf2 regulation and subsequent cellular protection conferred by DMF and its bioactive metabolite, monomethyl fumarate (MMF). For this thesis study, transcriptional profiling studies following oral administration of DMF were conducted to characterize DMF pharmacodynamic responses in the central nervous system (CNS) and peripheral tissues to understand the functional effects of DMF in vivo as well as explore the necessity of Nrf2 in this process. Data from these studies confirm earlier findings that DMF activates transcription of Nrf2 target genes in the CNS and periphery; however, tissue-specific gene expression was also observed, indicating additional levels of transcriptional control beyond Nrf2 activation. These findings suggest that there may be unique cytoprotective and immunomodulatory capabilities of DMF within specific tissues. In the CNS, a novel Nrf2 transcriptional target gene OSGIN1 was identified to be significantly upregulated following DMF treatment in vivo; however, the contribution of this gene to the pharmacodynamic properties of DMF or MMF has not been previously described. Therefore, the in vitro effects of MMF on OSGIN1 expression were characterized, and the necessity of OSGIN1 in mediating cytoprotective effects against toxic oxidative stress in human astrocytes was evaluated. These data identify a potential mechanism for MMF-mediated cytoprotection in human astrocytes that function in an OSGIN1 and p53-dependent manner. Overall, the experiments described in this dissertation allow for a broader understanding of endogenous cellular protection and how it can be used to combat CNS disorders.