科研之友
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摘要
Loss-of-function mutations in the DJ-1 gene are linked to rare autosomal recessive forms of parkinsonism. In Drosophila, two DJ-1 orthologs have been identified, DJ-1 alpha and DJ-1 beta. Several studies have shown that DJ-1 beta mutant flies are viable and fertile but exhibit age-dependent locomotor defects, shortened life span, and enhanced sensitivity to toxins that induce oxidative stress response compared to control flies. We also demonstrated that long-term dietary supplementation with antioxidant compounds was effective at increasing life-span values of DJ-1 beta mutants. These results, together with high levels of oxidative stress markers detected in newly eclosed DJ-1 beta mutant flies compared to controls, led to the proposal that the life-span phenotype was in part due to defects in the oxidative stress response. To further demonstrate this assumption, we analyzed in detail several markers of oxidative stress in control and DJ-1 beta mutant flies, either untreated or treated with antioxidant compounds. First, we quantified global reactive oxygen species (ROS) as well as H2O2 production; next we measured the activity of several enzymes that respond to oxidative stress such as catalase and superoxide dismutase; and finally we determined protein oxidative damage. Our results showed that DJ-1 beta mutants exhibit elevated ROS production and protein oxidative damage as well as decreased antioxidant enzyme activity compared to control flies of the same age, which is consistent with the proposed protective role of DJ-1 beta against oxidative stress. We found that supplementation with either alpha-tocopherol or the general antioxidant compound ascorbic acid (vitamin C) increased catalase activity and decreased H2O2 and oxidized protein levels in DJ-1 beta mutants and control flies, but it led to decreased superoxide dismutase activity, maybe as a consequence of a global reduction in oxidative stress. However, alpha-tocopherol supplementation specifically reduced global ROS production in DJ-1 beta mutant flies. This study confirms the important role of DJ-1 beta in oxidative stress response in Drosophila,. especially at the level of H2O2 detoxification, and provides evidence that early antioxidant supplementation is an effective treatment to suppress phenotypes in DJ-1 beta mutants partly by reducing oxidative damage.
- 出版日期2013-8
