Unraveling the role of Nrf2 in dopaminergic neurons: a review of oxidative stress and mitochondrial dysfunction in Parkinson’s disease

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcriptional factor, involved in the regulation of countenance of various anti-oxidant enzymes and cytoprotective genes that respond to mitochondrial dysfunctions, oxidative stress, and neuroinflammation, thus potentially contributing to several neurodegenerative diseases (NDDs), including Parkison’s disease (PD). PD is the second most prevalent progressive NDD, characterized by gradual neuronal death in substantia nigra pars compacta (SNpc), depletion of dopamine level, and a wide range of motor symptoms, including bradykinesia, tremor, tingling, and muscle fatigue. The etiopathology of PD is caused by multifactorial intertwined with the onset and progression of the disease. In this context, Nrf2 exhibits neuroprotective action by preserving dopaminergic neurons in the striatum and retarding the disease progression; thus, Nrf2 activation plays a crucial role in PD. Additionally, Nrf2 binds with the antioxidant response element, which is located in the promoter region of most of the genes that are responsible for coding antioxidant enzymes. Moreover, protein kinase C (PKC) mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) are also involved in the regulation of Keap1 pathway-mediated Nrf2 activation. As Nrf2 revealed its defensive and protective role in the central nervous system (CNS), it is gaining enough interest in treating PD. The treatments that are currently available are intended to alleviate the symptoms of PD; however, they are unable to halt the progression and severity of the disease. Therefore, in this review we delve deeper into various molecular mechanisms associated with oxidative stress, mitochondrial dysfunction, and neuroinflammation in PD. Additionally, we elaborated on the substantial role that NRF2 plays in mitigating these adverse effects and its potential as a therapeutic target.