1.Introduction
Parkinson’s disease (PD) is the second most prevalent multifactorial progressive neurodegenerative disorder, following Alzheimer’s disease, with no currently available curative interventions[1, 2]. The main pathology of PD is characterized by progressive degeneration of dopamine neurons in the substantia nigra (SN), a significant decrease in striatal dopamine levels, and progressive dysfunction of the body’s motor system[3, 4]. Accumulating evidence from human studies and various experimental models of PD suggests that oxidative stress and mitochondrial dysfunction play pivotal roles in this pathological process[5-7]. Therefore, targeting reduction of oxidative stress, enhancement of mitochondrial function, and maintenance of autophagy homeostasis help devise strategies to prevent or delay the progression of PD[8-11].
Nuclear Factor-Erythroid Factor 2 (Nrf2) is an important transcription factor that regulates the expression of large number of genes in healthy and disease states[12, 13]. Nrf2 regulates oxidative stress, mitochondrial biogenesis, mitochondrial autophagy, autophagy and mitochondrial function in peripheral nervous system and central nervous system[14, 15]. In response to conditions of oxidative stress, Nrf2 dissociates from Kelch - like ECH - associated protein - 1(Keap1) and translocates into the nucleus, where it binds to antioxidant response elements (AREs), thereby initiating the transcriptional activation of downstream antioxidant enzymes such as heme oxygenase 1 (HO-1), superoxide dismutase (SOD), glutamate cysteine ligase (GCL), and NAD(P)H quinone oxidoreductase 1 (NQO1)[16]. The antioxidant enzymes subsequently fulfill an antioxidative function. Recent studies have showed the involvement of Nrf2 in the autophagy pathway[17]. The activation of Nrf2 triggers autophagy through Sequestosome 1 (SQSTM1, p62), which directly interacts with Keap1 and facilitates its degradation via the autophagic process[18, 19]. Interestingly, when Nrf2 is largely translocated into the nucleus, it also upregulates the transcription of autophagy-related genes, including p62 and PINK1 (PTEN - induced kinase 1), whose promoters ARE included in the ARE nucleotide sequence, thereby forming a p62 - Keap1 - Nrf2 positive feedback loop[20]. (Fig. 1)