Roles of Drosophila DJ-1 in Survival of Dopaminergic Neurons and Oxidative Stress

Neurogenetics Branch MSC 3705, Building 35, Room 2A 1002 NINDS, National Institutes of Health, Bethesda, Maryland 20892, USA.
Current Biology (Impact Factor: 9.57). 10/2005; 15(17):1578-82. DOI: 10.1016/j.cub.2005.07.036
Source: PubMed


The loss of dopaminergic neurons in the substantia nigra is the pathological hallmark of Parkinson's disease (PD). While the etiology of sporadic PD remains elusive, an inherited form of early-onset familial PD is linked to mutations of DJ-1. To understand the biological function of DJ-1 and its relevance to the pathogenesis of PD, we investigated the function of DJ-1 using Drosophila. Drosophila possesses two homologs of human DJ-1: DJ-1alpha and DJ-1beta. We found that DJ-1alpha is expressed predominantly in the testis, while DJ-1beta is ubiquitously present in most tissues, resembling the expression pattern of human DJ-1. Loss-of-function DJ-1beta mutants demonstrated an extended survival of dopaminergic neurons and resistance to paraquat stress, but showed acute sensitivity to hydrogen peroxide treatment. We showed a compensatory upregulation of DJ-1alpha expression in the brain of the DJ-1beta mutant and demonstrated that overexpression of DJ-1alpha in dopaminergic neurons is sufficient to confer protection against paraquat insult. These results suggest that Drosophila homologs of DJ-1 play critical roles in the survival of dopaminergic neurons and response to oxidative stress.

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Available from: Sarat Yenisetti, Aug 07, 2015
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    • "Yes (Lavara-Culebras and Paricio, 2007; Menzies et al., 2005; Meulener et al., 2005; Park et al., 2005) Yes (Kim et al., 2005; Menzies et al., 2005; Meulener et al., 2005; Yang et al., 2005) "
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    ABSTRACT: Parkinson's disease is an incurable neurodegenerative disease. Most cases of the disease are of sporadic origin, but about 10% of the cases are familial. The genes thus far identified in Parkinson's disease are well conserved. Drosophila is ideally suited to study the molecular neuronal cell biology of these genes and the pathogenic mutations in Parkinson's disease. Flies reproduce fast and their elaborate and modern genetic tools in combination with their small size allows researchers to analyze identified cells and neurons in large numbers of animals. Furthermore, fruit flies recapitulate many of the organellar and molecular defects also seen in patients, and these defects often result in clear phenotypes also at the level of locomotion and behavior, facilitating genetic modifier screens. Hence, Drosophila has played a prominent role in Parkinson's disease research and has provided invaluable insight into the molecular mechanisms of this disease. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Feb 2015 · Experimental Neurology
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    • "Unlike mammals, which contain a single DJ-1 gene, Drosophila melanogaster has two DJ-1 genes (DJ-1α and DJ-1β) [44], which differ in tissue distribution. DJ-1α is detected primarily in the testes from the pupal to the adult stage, whereas DJ-1β is found in most tissues from embryo to adults [33,44,45]. Similar to Drosophila, C. elegans has two DJ-1 genes (cDJR-1.1 and cDJR-1.2), "
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    ABSTRACT: Reactive carbonyl species (RCS), such as methylglyoxal (MG) and glyoxal (GO), are synthesized as toxic metabolites in living systems. Mechanisms of RCS detoxification include the glutathione (GSH)-dependent system consisting of glyoxalase I (GLO1) and glyoxalase II (GLO2), and GSH-independent system involving glyoxalase III (GLO3). Hsp31 and DJ-1 proteins are weakly homologous to each other and belong to two different subfamilies of the DJ-1/Hsp31/PfpI superfamily. Recently, the Escherichia coli Hsp31 protein and the DJ-1 proteins from Arabidopsis thaliana and metazoans have been demonstrated to have GLO3 activity. We performed a systematic survey of homologs of DJ-1 and Hsp31 in fungi. We found that DJ-1 proteins have a very limited distribution in fungi, whereas Hsp31 proteins are widely distributed among different fungal groups. Phylogenetic analysis revealed that fungal and metazoan DJ-1 proteins and bacterial YajL proteins are most closely related and together form a sister clade to bacterial and fungal Hsp31 proteins. We showed that two Schizosaccharomyces pombe Hsp31 proteins (Hsp3101 and Hsp3102) and one Saccharomyces cerevisiae Hsp31 protein (ScHsp31) displayed significantly higher in vitro GLO3 activity than S. pombe DJ-1 (SpDJ-1). Overexpression of hsp3101, hsp3102 and ScHSP31 could confer MG and GO resistance on either wild-type S. pombe cells or GLO1 deletion of S. pombe. S. pombe DJ-1 and Hsp31 proteins exhibit different patterns of subcellular localization. Our results suggest that fungal Hsp31 proteins are the major GLO3 that may have some role in protecting cells from RCS toxicity in fungi. Our results also support the view that the GLO3 activity of Hsp31 proteins may have evolved independently from that of DJ-1 proteins.
    Full-text · Article · Apr 2014 · BMC Evolutionary Biology
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    • "Drosophila melanogaster has been successfully used to uncover molecular pathways underlying pathobiology caused by the loss of several PD-associated genes, including pink1, parkin, and DJ-1 [18]–[22]. To generate a fly model for mortalin-associated PD, we used a targeted knockdown of Hsc70-5, the Drosophila homolog of human mortalin. "
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    ABSTRACT: Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson's disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism.
    Full-text · Article · Dec 2013 · PLoS ONE
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