Oxidative modification impairs SERCA activity in Drosophila and human cell models of Parkinson's disease.

DJ-1 is a causative gene for familial Parkinson's disease (PD) with different functions, standing out its role against oxidative stress (OS). Accordingly, PD model flies harboring a mutation in the DJ-1β gene (the Drosophila ortholog of human DJ-1) show high levels of OS markers like protein carbonylation, a common post-translational modification that may alter protein function. To increase our understanding of PD pathogenesis as well as to discover potential therapeutic targets for pharmacological intervention, we performed a redox proteomic assay in DJ-1β mutant flies. Among the proteins that showed increased carbonylation levels in PD model flies, we found SERCA, an endoplasmic reticulum Ca channel that plays an important role in Ca homeostasis. Interestingly, several studies have supported the involvement of Ca dyshomeostasis in PD. Thus, we decided to study the relation between SERCA activity and PD physiopathology. Our results showed that SERCA enzymatic activity is significantly reduced in DJ-1β mutant flies, probably as a consequence of OS-induced carbonylation, as well as in a human cell PD model based on DJ-1-deficiency. Indeed, higher carbonylation levels of SERCA were also observed in DJ-1-deficient cells compared to controls. In addition, the specific activator of SERCA, CDN1163, was also able to restore PD-related phenotypes in both familial PD models by increasing SERCA activity. Taken together, our results indicate that impaired SERCA activity due to oxidative modification may play a role in PD physiopathology. Furthermore, we demonstrate that therapeutic strategies addressing SERCA activation could be beneficial to treat this disease as shown for CDN1163.