The Nrf2-mediated defense mechanism associated with HFE genotype limits vulnerability to oxidative stress-induced toxicity

There is considerable interest in gene and environment interactions in neurodegenerative diseases. The HFE (homeostatic iron regulator) gene variant (H63D) is highly prevalent in the population and has been investigated as a disease modifier in multiple neurodegenerative diseases. We have developed a mouse model to interrogate the impact of this gene variant in a model of paraquat toxicity. Using primary astrocytes, we found that the H67D-Hfe(equivalent of the human H63D variant) astrocytes are less vulnerable than the WT-Hfe astrocytes to paraquat-induced cell death, mitochondrial damage, and cellular senescence. We hypothesized that the Hfe variant-associated protection is a result of the activation of the Nrf2 antioxidant defense system and found a significant increase in Nrf2 levels after paraquat exposure in the H67D-Hfe astrocytes than the WT-Hfe astrocytes. Moreover, decreasing Nrf2 by molecular or pharmaceutical manipulation resulted in increased vulnerability to paraquat in the H67D-Hfe astrocytes. To further elucidate the role of Hfe variant genotype in neuroprotection mediated by astrocytes, we added media from the paraquat-treated astrocytes to differentiated SH-SY5Y neuroblastoma cells and found a significantly larger reduction in the viability when treated with WT-Hfe astrocyte media than the H67D-Hfe astrocyte media possibly due to higher secretion of IL-6 observed in the WT-Hfe astrocytes. To further explore the mechanism of Nrf2 protection, we measured NQO1, the Nrf2-mediated antioxidant, in primary astrocytes and found a significantly higher NQO1 level in the H67D-Hfe astrocytes. To consider the translational potential of our findings, we utilized the PPMI (Parkinson's Progression Markers Initiative) clinical database and found that, consistent with the mouse study, H63D-HFE carriers had a significantly higher NQO1 level in the CSF than the WT-HFE carriers. Consistent with our previous reports on H63D-HFE in disease, these data further suggest that HFE genotype in the human population impacts the antioxidant defense system and can therefore alter pathogenesis.