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

<div><p><i>DJ-1</i>, a Parkinson's disease (PD)–associated gene, has been shown to protect against oxidative stress in <i>Drosophila</i>. However, the molecular mechanism underlying oxidative stress-induced phenotypes, including apoptosis, locomotive defects, and lethality, in <i>DJ-1</i>-deficient flies is not fully understood. Here we showed that <i>Daxx-like protein</i> (<i>DLP</i>), a <i>Drosophila</i> homologue of the mammalian <i>Death domain-associated protein</i> (<i>Daxx</i>), was upregulated under oxidative stress conditions in the loss-of-function mutants of <i>Drosophila DJ-1β</i>, a <i>Drosophila</i> homologue of <i>DJ-1</i>. <i>DLP</i> overexpression induced apoptosis via the c-Jun N-terminal kinase (JNK)/<i>Drosophila</i> forkhead box subgroup O (dFOXO) pathway, whereas loss of <i>DLP</i> increased resistance to oxidative stress and UV irradiation. Moreover, the oxidative stress-induced phenotypes of <i>DJ-1β</i> mutants were dramatically rescued by <i>DLP</i> deficiency, suggesting that enhanced expression of <i>DLP</i> contributes to the <i>DJ-1β</i> mutant phenotypes. Interestingly, we found that dFOXO was required for the increase in <i>DLP</i> expression in <i>DJ-1β</i> mutants and that dFOXO activity was increased in the heads of <i>DJ-1β</i> mutants. In addition, subcellular localization of DLP appeared to be influenced by <i>DJ-1</i> expression so that cytosolic DLP was increased in <i>DJ-1β</i> mutants. Similarly, in mammalian cells, Daxx translocation from the nucleus to the cytosol was suppressed by overexpressed <i>DJ-1β</i> under oxidative stress conditions; and, furthermore, targeted expression of <i>DJ-1β</i> 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 <i>DJ-1</i>-associated PD.</p>