DJ-1 and SOD1 Act Independently in the Protection against Anoxia in Drosophila melanogaster

Abstract

Redox homeostasis is a vital process the maintenance of which is assured by the presence of numerous antioxidant small molecules and enzymes and the alteration of which is involved in many pathologies, including several neurodegenerative disorders. Among the different enzymes involved in the antioxidant response, SOD1 and DJ-1 have both been associated with the pathogenesis of amyotrophic lateral sclerosis and Parkinson’s disease, suggesting a possible interplay in their mechanism of action. Copper deficiency in the SOD1-active site has been proposed as a central determinant in SOD1-related neurodegeneration. SOD1 maturation mainly relies on the presence of the protein copper chaperone for SOD1 (CCS), but a CCS-independent alternative pathway also exists and functions under anaerobic conditions. To explore the possible involvement of DJ-1 in such a pathway in vivo, we exposed Drosophila melanogaster to anoxia and evaluated the effect of DJ-1 on fly survival and SOD1 levels, in the presence or absence of CCS. Loss of DJ-1 negatively affects the fly response to the anoxic treatment, but our data indicate that the protective activity of DJ-1 is independent of SOD1 in Drosophila, indicating that the two proteins may act in different pathways.

Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis: What the DJ-1 Protein Teaches Us

“…Always related to ALS, DJ-1 has been shown, in vitro, to bind copper [47][48][49] and to interact with and activate SOD1 through copper transfer [49,50], suggesting the possibility that the antioxidant activity of DJ-1 is mediated by SOD1. This hypothesis, however, needs further investigation since a recent study performed in Drosophila melanogaster was unable to confirm the participation of DJ-1 in the SOD1 maturation pathway in vivo [29], while the interaction between copper and DJ-1 was not detected in an NMR analysis performed in a cellular environment [51]. Always related to ALS, DJ-1 has been shown, in vitro, to bind copper [47][48][49] and to interact with and activate SOD1 through copper transfer [49,50], suggesting the possibility that the antioxidant activity of DJ-1 is mediated by SOD1.…”

“…As aforementioned, the most widely accepted function of DJ-1 is its protective role against excessive ROS levels. Accordingly, the overexpression of DJ-1 results in neuronal cytoprotection against oxidative damage, whereas DJ-1 deficiency leads to an increase in oxidative-stress-induced cell death, both in cell cultures and animal models [28][29][30][31][32][33][34][35][36]. In this regard, it has been suggested that DJ-1 may sense the cellular redox state through a highly conserved cysteine residue localized at position 106, contributing to the regulation of redox homeostasis [37].…”

“…Recently, using D. melanogaster as an in vivo model, we have demonstrated that the absence of DJ-1 affects adult fly survival under oxygen depletion [29], in line with a purported protective role of DJ-1 against hypoxia [27]. One of the key events occurring in response to hypoxia is the activation of the transcription factor Hypoxia-Inducible Factor-1α (HIF-1α), which otherwise, under normal oxygen tension, is constantly hydroxylated by the enzyme prolyl hydroxylase (PHD) to be recognized and labeled by the E3 ubiquitin ligase Von Hippel-Lindau (VHL) and then degraded at the proteasome [27] (Figure 2).…”