Drosophila DJ-1 decreases neural sensitivity to stress by negatively regulating Daxx-like protein through dFOXO

PLoS Genet. 2013 Apr;9(4):e1003412. doi: 10.1371/journal.pgen.1003412. Epub 2013 Apr 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing* / genetics
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Animals
  • Apoptosis / radiation effects
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila Proteins* / deficiency
  • Drosophila Proteins* / genetics
  • Drosophila Proteins* / metabolism
  • Forkhead Transcription Factors* / genetics
  • Forkhead Transcription Factors* / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mutation
  • Nerve Tissue Proteins* / deficiency
  • Nerve Tissue Proteins* / genetics
  • Nerve Tissue Proteins* / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Oxidative Stress* / genetics
  • Oxidative Stress* / radiation effects
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism
  • Parkinson Disease* / physiopathology
  • Radiation Tolerance / genetics
  • Ultraviolet Rays

Substances

  • Adaptor Proteins, Signal Transducing
  • DJ-1alpha protein, Drosophila
  • Daxx protein, Drosophila
  • Drosophila Proteins
  • FOXO protein, Drosophila
  • Forkhead Transcription Factors
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • JNK Mitogen-Activated Protein Kinases

Grant support

This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (2009-0071071 and 2010-0011418) (KSC) and by the 2009 Seoul Scholarship Foundation (SH). This research was also supported by the National Creative Research Initiatives Program (2010-0018291) from the Korean Ministry of Education, Science and Technology (JC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.