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

Abstract

Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases as strict regulation of integrated mitochondrial functions is essential for neuronal signaling, plasticity, and transmitter release. Many lines of evidence suggest that mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson's disease (PD). Several PD-associated genes interface with mitochondrial dynamics regulating the structure and function of the mitochondrial network. Mitochondrial dysfunction can induce neuron death through a plethora of mechanisms. Both mitochondrial dysfunction and neuroinflammation, a common denominator of PD, lead to an increased production of reactive oxygen species, which are detrimental to neurons. The transcription factor nuclear factor E2-related factor 2 (Nrf2, NFE2L2) is an emerging target to counteract mitochondrial dysfunction and its consequences in PD. Nrf2 activates the antioxidant response element (ARE) pathway, including a battery of cytoprotective genes such as antioxidants and anti-inflammatory genes and several transcription factors involved in mitochondrial biogenesis. Here, the current knowledge about the role of mitochondrial dysfunction in PD, Nrf2/ARE stress-response mechanisms, and the evidence for specific links between this pathway and PD are summarized. The neuroprotection of nigral dopaminergic neurons by the activation of Nrf2 through several inducers in PD is also emphasized as a promising therapeutic approach.

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.