Glutathione S-Transferase Omega 1 Activity Is Sufficient to Suppress Neurodegeneration in a Drosophila Model of Parkinson Disease

School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2012; 287(9):6628-41. DOI: 10.1074/jbc.M111.291179
Source: PubMed


A loss-of-function mutation in the gene parkin causes a common neurodegenerative disease that may be caused by mitochondrial dysfunction. Glutathione S-transferase Omega (GSTO) is involved in cell defense mechanisms, but little is known about the role of GSTO in the progression
of Parkinson disease. Here, we report that restoration of Drosophila GSTO1 (DmGSTO1), which is down-regulated in parkin mutants, alleviates some of the parkin pathogenic phenotypes and that the loss of DmGSTO1 function enhances parkin mutant phenotypes. We further identified the ATP synthase β subunit as a novel in vivo target of DmGSTO1. We found that glutathionylation of the ATP synthase β subunit is rescued by DmGSTO1 and that the expression
of DmGSTO1 partially restores the activity and assembly of the mitochondrial F1F0-ATP synthase in parkin mutants. Our results suggest a novel mechanism for the protective role of DmGSTO1 in parkin mutants, through the regulation of ATP synthase activity, and provide insight into potential therapies for Parkinson disease

Download full-text


Available from: Kiyoung Kim, Jul 13, 2015
  • Source
    • "All of them are induced by PQ, but particularly TtGSTM9 (z_61_fold) (Fig. 7 and Table S4). In human and animal cells, by using both GST enzymes activity assessment and GST gene expression analysis (qRT-PCR), a selective induction of certain GSTs after PQ treatment has been reported (Ahmad et al., 2013; Kim et al., 2012). From these results, the role of glutathione conjugation and elimination of certain products derived from lipid peroxidation caused by this herbicide, has been attributed to these enzymes (Ahmad et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: •Tetrahymena thermophila is an eukaryotic microorganism very resistant to paraquat.•Superoxide production is significantly increased under paraquat exposure.•ROS induction is proportional to paraquat concentration, when toxicity does not generates a high cell mortality.•Mitochondria may be the main target of paraquat toxicity in T. thermophila.•An up-regulation of gene expression encoding critical antioxidant enzymes is involved in the cell response against this toxic pollutant.
    Full-text · Article · Feb 2016 · Chemosphere
  • Source
    • "We also tested DAergic neuronal loss in a null allele of parkin ( park 1 ) in which the PPL1 DA cluster has been also reported to be primarily affected in 20 - day - old flies ( Whitworth et al . 2005 ; Trinh et al . 2010 ; Kim et al . 2012 ) . These flies presented the classical muscular and"
    [Show abstract] [Hide abstract]
    ABSTRACT: Drosophila melanogaster has contributed significantly to the understanding of disease mechanisms in Parkinson's disease (PD) as it is one of the very few PD model organisms that allows the study of age-dependent behavioral defects, physiology and histology, and genetic interactions among different PD-related genes. However, there have been contradictory results from a number of recent reports regarding the loss of dopaminergic neurons in different Parkinson's disease fly models. In an attempt to reevaluate and clarify this issue, we have examined three different genetic (α-synuclein, Pink1, parkin) and two toxin-based (rotenone and paraquat) models of the disease for neuronal cell loss. Our results showed no dopaminergic neuronal loss in all models tested. Despite this surprising result, we found additional phenotypes showing the dysfunctional status of the dopaminergic neurons in most of the models analyzed. A common feature found in most models is a quantifiable decrease in the fluorescence of a GFP reporter gene in dopaminergic neurons that correlates well with other phenotypes found for these models and can be reliably used as a hallmark of the neurodegenerative process when modeling diseases affecting the dopaminergic system in Drosophila.This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2014 · Journal of Neurochemistry
  • Source
    • "When GST O1, which has two distinct alleles, GST O1A and GST O1B, is deleted, there is an increased sensitivity to the xenobiotic paraquat [162] [164]. The reexpression of GST O1A in the null mutant eliminates the sensitivity of the PPL DA neurons to paraquat and suppresses phospho-JNK activity, which is implicated in apoptosis [163]. A number of polymorphisms in the leucine-rich-repeat kinase 2 (LRRK2) gene have been shown to confer PD in humans [165– 167]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been established that oxidative stress, defined as the condition when the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson's disease. Glutathione is a ubiquitous thiol tripeptide that acts alone, or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals and peroxynitrites. In this review, we examine the synthesis, metabolism and functional interactions of glutathione, and discuss how this relates to protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson's disease.
    Full-text · Article · May 2013 · Free Radical Biology and Medicine
Show more