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)