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

Soojin Hwang; Saera Song; Yoon Ki Hong; Gahee Choi; Yoon Seok Suh; Seung Yeop Han; Minjung Lee; Seung Hwan Park; Jang Ho Lee; Soojin Lee; Se Min Bang; Yuji Jeong; Won-Ju Chung; Im-Soon Lee; Gilsang Jeong; Jongkyeong Chung; Kyoung Sang Cho

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-1b, 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-1βmutant 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-1βmutants. In addition, subcellular localization of DLP appeared to be influenced by DJ-1 expression so that cytosolic DLP was increased in DJ-1βmutants. Similarly, in mammalian cells, Daxx translocation from the nucleus to the cytosol was suppressed by overexpressed DJ-1βunder oxidative stress conditions; and, furthermore, targeted expression of DJ-1βto mitochondria efficiently inhibited the Daxx translocation. Taken together, our findings demonstrate that DJ-1βprotects 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.

PARKINSON'S disease; OXIDATIVE stress; DROSOPHILA; APOPTOSIS; GENE expression

PLoS Genetics, 2013, Vol 9, Issue 4, p1

1553-7390

Academic Journal

10.1371/journal.pgen.1003412