Effects of pharmacological agents on the lifespan phenotype of Drosophila DJ-1β mutants

Abstract

Mutations in the DJ-1 gene cause autosomal recessive, early-onset Parkinsonism. The DJ-1 protein exerts a protective role against oxidative stress damage, working as a cellular oxidative stress sensor, and it seems to regulate gene expression at different levels. In Drosophila, two DJ-1 orthologs have been identified: DJ-1alpha and DJ-1beta. Several studies have shown that loss of DJ-1beta function causes Parkinson's disease (PD)-like phenotypes in flies such as age-dependent locomotor defects, reduced lifespan, and enhanced sensitivity to toxins that induce oxidative stress, like the herbicide paraquat. However, no dopaminergic neurodegeneration is observed. These results suggested that both locomotor and lifespan phenotypes could be either related to defects in oxidative stress response, or in dopaminergic physiology as proposed in mice models. In this study, we have employed pharmacological approaches to modify the lifespan phenotype of DJ-1beta mutant flies. We have assessed the effects of chronic treatments with antiparkinsonian drugs as well as with antioxidant compounds on such phenotype finding that only antioxidants show statistically significant beneficial effects on DJ-1beta mutants' lifespan. These results strongly suggest that oxidative stress plays a causal role in the lifespan phenotype of DJ-1beta mutants. Consistent with this, we find that loss of DJ-1beta function results in cellular accumulation of reactive oxygen species (ROS) in adult brains, elevated levels of lipid peroxidation and an increased catalase enzymatic activity, thus indicating the existence of high oxidative stress levels in DJ-1beta mutants and confirming the essential function of the DJ-1beta protein in protecting the organism against oxidative insults. Our study further shows that the lifespan phenotype of DJ-1beta mutant flies is amenable to pharmacological intervention, and validates Drosophila as a valuable model for testing and identifying new drugs with therapeutic potential for PD.

Neuroprotection and repair of 3′-blocking DNA ends by glaikit (gkt) encoding Drosophila tyrosyl-DNA phosphodiesterase 1 (TDP1)

“…The longevity assay was performed as described (55). One hundred eighty 1-to 2-d-old TDP1 mutants or control flies were collected under brief CO 2 anesthesia.…”

Melatonin: a possible link between the presence of artificial light at night and reductions in biological fitness

“…Melatonin supplementation experiments generally reveal a positive effect of melatonin on survival in both vertebrates and invertebrates [67][68][69][70]. Similarly, a number of studies have found melatonin plays a fundamental role in immune-modulation, but this has been explored almost exclusively in vertebrates (for recent reviews see [71][72][73]).…”

Parkinson’s Disease: Insights from Drosophila Model

“…Compounds with antioxidant and anti-inflammatory properties such as celastrol and minocycline conferred potent DA neuroprotection in RNAi DJ-1α mutants [176]. We have also recently demonstrated that chronic treatments with antioxidant compounds are able to modify the lifespan phenotype of DJ-1β mutant flies, thus suggesting that oxidative stress plays a causal role in such phenotype [177]. It is known that rapamycin is a small molecule inhibitor of TOR signaling that has been shown to lead to 4E-BP hypophosphorylation in vitro and in vivo [178,179].…”

“…It is known that grape extracts contain several polyphenols, compounds with antioxidant properties [175]. Other drosophila PD models in which treatments with antioxidant compounds have been shown to be beneficial are those involving the DJ-1α and DJ-1β genes [176,177]. Compounds with antioxidant and anti-inflammatory properties such as celastrol and minocycline conferred potent DA neuroprotection in RNAi DJ-1α mutants [176].…”