The Nrf2/ARE Pathway: A Promising Target to Counteract Mitochondrial Dysfunction in Parkinson's Disease

Figure 1

The role of the Nrf2 pathway in PD pathogenesis. In the case of oxidative damage, mitochondria produce increased amounts of ROS. Then, ROS activate Nrf2 bound to Keap1 in the cytoplasm, and it translocates into the nucleus to transactivate the transcription of ARE-bearing genes, which in turn activates the antioxidant defense system and mitochondrial biogenesis. In this pathway, PD-related genes are also involved. DJ-1 is found to inhibit oxidative damage in mitochondria. Another PD-related gene is PINK, which prevents impaired membrane potential of mitochondria and prevents apoptosis by counteracting cytochrome c release that leads to apoptosis of nigral cells. Lastly, Parkin was found to inhibit cytochrome c release that leads to caspase activation and apoptosis of nigral cells. Ubiquitin-interacting p62 also has a role in Nrf2 activation. It normally plays a role in transportation of ubiquitinated proteins to autophagosome. p62 was found to be interacting with Keap1 and transports it for autophagic degradation and provides indirect activation of Nrf2. p62 also has ARE in its promoter region which creates a positive feedback loop between Nrf2 and p62.