Drosophila DJ-1 Decreases Neural Sensitivity to Stress by Negatively Regulating Daxx-Like Protein through dFOXO

Dj-1,a parkinson's disease (pd)-associated gene,has been shown to protect against oxidative stress in drosophila. however,the molecular mechanism underlying oxidative stress-induced phenotypes,including apoptosis,locomotive defects,and lethality,in dj-1-deficient flies is not fully understood. here we showed that daxx-like protein (dlp),a drosophila homologue of the mammalian death domain-associated protein (daxx),was upregulated under oxidative stress conditions in the loss-of-function mutants of drosophila dj-1β,a drosophila homologue of dj-1. dlp overexpression induced apoptosis via the c-jun n-terminal kinase (jnk)/drosophila forkhead box subgroup o (dfoxo) pathway,whereas loss of dlp increased resistance to oxidative stress and uv irradiation. moreover,the oxidative stress-induced phenotypes of dj-1β mutants were dramatically rescued by dlp deficiency,suggesting that enhanced expression of dlp contributes to the dj-1β mutant phenotypes. interestingly,we found that dfoxo was required for the increase in dlp expression in dj-1β mutants and that dfoxo activity was increased in the heads of dj-1β mutants. in addition,subcellular localization of dlp appeared to be influenced by dj-1 expression so that cytosolic dlp was increased in dj-1β mutants. similarly,in mammalian cells,daxx translocation from the nucleus to the cytosol was suppressed by overexpressed dj-1β under oxidative stress conditions; and,furthermore,targeted expression of dj-1β to mitochondria efficiently inhibited the daxx translocation. taken together,our findings demonstrate that dj-1β protects flies against oxidative stress- and uv-induced apoptosis by regulating the subcellular localization and gene expression of dlp,thus implying that daxx-induced apoptosis is involved in the pathogenesis of dj-1-associated pd. © 2013 hwang et al.