title: Drosophila DJ-1 decreases neural sensitivity to stress by negatively regulating Daxx-like protein through dFOXO.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul, Republic of Korea.
authors.forename: Soojin
authors.initials: S
authors.lastname: Hwang
authors.forename: Saera
authors.initials: S
authors.lastname: Song
authors.forename: Yoon Ki
authors.initials: YK
authors.lastname: Hong
authors.forename: Gahee
authors.initials: G
authors.lastname: Choi
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Suh
authors.forename: Seung Yeop
authors.initials: SY
authors.lastname: Han
authors.forename: Minjung
authors.initials: M
authors.lastname: Lee
authors.forename: Seung Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Jang Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Soojin
authors.initials: S
authors.lastname: Lee
authors.forename: Se Min
authors.initials: SM
authors.lastname: Bang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Jeong
authors.forename: Won-Ju
authors.initials: WJ
authors.lastname: Chung
authors.forename: Im-Soon
authors.initials: IS
authors.lastname: Lee
authors.forename: Gilsang
authors.initials: G
authors.lastname: Jeong
authors.forename: Jongkyeong
authors.initials: J
authors.lastname: Chung
authors.forename: Kyoung Sang
authors.initials: KS
authors.lastname: Cho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000528:radiation effects; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011836:Radiation Tolerance / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C506878:DJ-1alpha protein, Drosophila; C526347:Daxx protein, Drosophila; D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D048031:JNK Mitogen-Activated Protein Kinases