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.

Compromised MAPK signaling in human diseases: an update

“…Flies with a loss-offunction mutation of DJ-1 manifest up-regulation of Daxx-like protein (DLP), a Drosophila Daxx homolog, in response to oxidative stress, resulting in apoptotic cell death through activation of JNK and FOXO signaling pathways (Hwang et al 2013). Mammalian DJ-1 interacts directly with SHP1, a Src homology 2 domain-containing protein tyrosine phosphatase, as well as with signal transducer and activator of transcription 1 (STAT1) (Kim et al 2013b).…”

FOXO transcription factors: key regulators of cellular quality control

“…It will be important to determine if PINK1 can also act upstream of FOXO in mammals in a feedback loop, and determine whether the ability of FOXO3 to promote mitophagy delays neurodegeneration in cellular or organismal models for Parkinson’s diseases in mammals. While FOXO plays a protective role in flies that are deficient for PARKIN (PARK2) , it has also been reported to induce apoptosis in dopaminergic neurons under conditions of oxidative stress triggered by loss of DJ-1 β ( PARK7 ), another gene involved in Parkinson’s disease, in Drosophila [51]. Thus, FOXO may act as an oxidative stress rheostat in dopaminergic neurons, playing a protective role when oxidative stress levels are relatively low, but promoting cell death when the oxidative stress load is high.…”

“…Alternatively, the differences observed may be due to disparities in experimental approaches. Thus far, experiments assessing the role of FOXOs in Parkinson’s disease have been performed in different cell types (fibroblasts, MCF-7 cells or dopaminergic neurons) [48, 50] or genetic conditions ( PINK1 or PARK7 mutants) [49, 51]. In addition, some studies have used overexpression of wild type or mutant forms of exogenous FOXOs to determine function [48, 50].…”

Epigenetic Changes in Neurodegenerative Diseases

“…The transcriptional dysregulation is also reported in other types of neurodegenerative diseases. For example, a recent study proposed that DJ-1 associated with PD can regulate the FOXO transcription factor pathway (Hwang et al, 2013). …”