Drosophila DJ-1 Decreases Neural Sensitivity to Stress by Negatively Regulating Daxx-Like Protein through dFOXO e1003412

• Published in: PLoS genetics Vol. 9; no. 4
• Main Authors: Hwang, Soojin, Song, Saera, Hong, Yoon Ki, Choi, Gahee, Suh, Yoon Seok, Han, Seung Yeop, Lee, Minjung, Park, Seung Hwan, Lee, Jang Ho, Lee, Soojin, Bang, Se Min, Jeong, Yuji, Chung, Won-Ju, Lee, Im-Soon, Jeong, Gilsang, Chung, Jongkyeong, Cho, Kyoung Sang
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 01.04.2013
• Subjects: Apoptosis; Colleges & universities; Drosophila; Insects; Kinases; Mitochondrial DNA; Nitric oxide; Oxidative stress; Parkinson's disease; Proteins; United States > US; California
• ISSN: 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003412

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.