Redox modulatory role of DJ-1 in Parkinson's disease.

Abstract

In particular, oxidative stress, generated by excessive reactive oxygen species (ROS), plays a major role in the neurodegenerative component of Parkinson's disease (PD) in aged neurons. DJ-1 (PARK7) is a key factor for maintaining redox homeostasis and modulation of mitochondrial function to preserve the cellular survival pathways. DJ-1 also plays a role in redox signaling independently of its antioxidant capacity by preventing the redox chain disulfide formation and stabilizing the master regulator of cellular antioxidant defense, Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2). In the DJ-1 or Nrf2 axis, expression of key antioxidant enzymes (glutathione peroxidase (GPx), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1) in response to oxidative stress is increased, and decreased neuronal damage resulting from oxidative stress is achieved. It has been demonstrated that DJ-1 functions as an oxidative stress sensor, and mutations like L166P cause loss of antioxidant activity and increased Reactive Oxygen Species (ROS) accumulation with subsequent mitochondrial dysfunction in dopaminergic neurons. The highly conserved cysteine residue at position 106 (Cys106) of DJ-1 becomes stepwise oxidized (Cys-SOH → Cys-SO₂H → Cys-SO₃H), functioning as a redox sensor as well as redox modulator of cellular stress responses. Furthermore, by protecting against α-synuclein aggregation, DJ-1 also protects in models lacking DJ-1, whereby DJ-1 deficiency promotes protein misfolding and neurotoxicity. In addition, DJ-1 participates in regulating neuroinflammation since its diminution provokes NF-κB-mediated exacerbation of proinflammatory cytokine production, leading to neuronal death. Oxidized DJ-1 (OxiDJ-1) is generated in aging brains, particularly in the substantia nigra (SN), and is correlated with PD progression both as a biomarker for disease monitoring and diagnosis of PD early in its course. The therapeutic strategies aimed at DJ-1 include small molecular activators, protein supplementation (Tat-DJ-1, ND-13), and gene therapy aiming to restore the neuroprotective function of DJ-1. Since DJ-1 is multitasking to protect neurons from oxidative damage, mitochondrial dysfunction, and even inflammation, it remains a promising therapeutic target. This review highlights the molecular mechanisms through which DJ-1 can protect from PD and aging-related neurodegeneration and has potential utility as a biomarker or therapeutic target.