Binding of Nrf2 with ARE
An activation of Nrf2 alone is not sufficient to increase the levels of antioxidant enzymes and phase-2-detoxifying enzymes. Activated Nrf2 must bind with ARE in the nucleus for increasing the expression of target genes for antioxidant enzymes and phase-2-detoxyfying enzymes. This binding ability of Nrf2 with ARE was impaired in aged rats and this defect was restored by supplementation with alpha- lipoic acid . It is unknown whether the binding ability of Nrf2 with ARE is impaired in PD.
Regulation of the Levels and Activity of Nrf2
Nrf2 regulates Keap1 levels by controlling its transcription, whereas Keap1 regulates Nrf2 levels by controlling its degradation by proteasome . Immediate early response-3 (IER-3) gene, a multifunctional stress response gene, also regulates Nrf2 activity. Deletion of IER-3 gene increases Nrf2 activity, whereas overexpression of IER-3 decreases it .
Epigenetically Regulation of the Levels of Nrf2
The levels of Nrf2 are regulated epigenetically by methylation of CpG (cytosine- phosphate-guanosine) and acetylation of histone3. Hypermethylation of CpG  and hyperacetylation of histone3  increase the expression of Nrf2, whereas hypomethylation of CpG and hypoacetylation of histone3 decrease it. Therefore, any agent that can cause hypermethylation of CpG or hyperacetylation of histone3 could be useful in prevention and improved management of PD.