Abstract
DJ-1 plays an important role in antioxidant defenses, and a reactive cysteine at position 106 (Cys106) of DJ-1, a critical residue of its biological function, is oxidized under oxidative stress. DJ-1 oxidation has been reported in patients with Parkinson’s disease (PD), but the relationship between DJ-1 oxidation and PD is still unclear. In the present study using specific antibody for Cys106-oxidized DJ-1 (oxDJ-1), we analyzed oxDJ-1 levels in the brain and peripheral tissues in young and aged mice and in a mouse model of PD induced using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). OxDJ-1 levels in the brain, heart, and skeletal muscle were high compared with other tissues. In the brain, oxDJ-1 was detected in PD-related brain sites such as the substantia nigra (SN) of the midbrain, olfactory bulb (OB), and striatum. In aged wild-type mice, oxDJ-1 levels in the OB, striatum, and heart tended to decrease, while those in the skeletal muscle increased significantly. Expression of dopamine-metabolizing enzymes significantly increased in the SN and OB of aged DJ-1−/− mice, accompanied by a complementary increase in glutathione peroxidase 1. MPTP treatment concordantly changed oxDJ-1 levels in PD-related brain sites and heart. These results indicate that the effects of physiological metabolism, aging, and neurotoxin change oxDJ-1 levels in PD-related brain sites, heart, and skeletal muscle where mitochondrial load is high, suggesting a substantial role of DJ-1 in antioxidant defenses and/or dopamine metabolism in these tissues.
Highlights
DJ-1, known as PARK7, is a causative gene of a familial form of Parkinson’s disease (PD)[1]
Western blot analysis of DJ-1 suggested that DJ-1 protein levels were high in brain and skeletal muscle, and the highest were in liver, lung, and pancreas (Fig. 1a)
Analysis of oxidized DJ-1 (oxDJ-1) levels in the brain and peripheral tissues suggests that the brain is rich in oxDJ-1, followed by skeletal muscle and heart (Fig. 1a)
Summary
DJ-1, known as PARK7, is a causative gene of a familial form of Parkinson’s disease (PD)[1]. Its product DJ-1 plays an important role in antioxidant defenses[2]: the loss of DJ-1 function increases sensitivity to oxidative stress-induced cell death. DJ-1 regulates signal mediators of oxidative stress, such as PTEN and ASK1, via direct interactions with these proteins[6]. It is thought that DJ-1 acts as an oxidative stress sensor, detecting cellular redox status through the oxidation of Cys[106] and altering the activity of signal mediators and the expression levels of genes involved in antioxidant defenses[8,14]. Post-mortem cardiac samples show decreased levels of axons expressing TH, which acts as a marker for sympathetic axons in peripheral tissues, indicating degeneration of the cardiac nerves in PD patients[22]. Meta-iodobenzylguanidine (MIBG), an analogue of noradrenaline, is actively taken up and stored in sympathetic nerves, and cardiac uptake of radiolabeled MIBG has been used for the diagnosis of PD23
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