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 F(1)F(0)-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 neurodegeneration.

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Available from: Kiyoung Kim, Jul 13, 2015
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    • "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"
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    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.
    Journal of Neurochemistry 07/2014; 131(3). DOI:10.1111/jnc.12818 · 4.28 Impact Factor
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    • "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]. "
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    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.
    Free Radical Biology and Medicine 05/2013; 62. DOI:10.1016/j.freeradbiomed.2013.05.001 · 5.74 Impact Factor
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    ABSTRACT: Objectives : Hippocampus, a region of temporal lobe, plays an important role in the pathogenic mechanisms of brain diseases such as Alzheimer's disease, depression and temporal lobe epilepsy. This research is designed to investigate hippocampal changes after acupuncture stimulation at Shinmun(HT7) using 2-dimensional gel electrophoresis(2-DE). Methods : On postnatal-day 15, rat pups were randomly devided into Normal(NOR) or HT7 group. All of Pups kept with their mothers for 7 days, but pups in HT7 group received acupuncture stimulation at HT7 daily. On postnatal-day 21, hippocampus of each rat pup was dissceted 30 minutes after last acupuncture stimulation and the protein expressions were investigated using 2-DE. Results : After acupuncture stimulation at HT7, expression of 20 proteins were significantly increased. Succinate semialdehyde dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase-like, transketolase, aconitate hydratase and phosphoglucomutase-1 were related to glucose methabolism. Eukaryotic initiation factor(eIF) 4A-II, eIF 4A-III, mitochondrial Tu translation elongation factor and chain A of crystal structure of the 70-Kda heat shock cognate protein involve in the protein synthesis in ribosome. Tubulin -4 chain, tubulin T -15 and tubulin -1B chain comprise cytoskeleton. Glutathione S-transferase(GST) -1, GST P and GST Yb-3 can reduce oxidative stress. -soluble N-ethylmaleimide-sensitive fusion protein attachment protein is required for vesicular transport between the endoplasmic reticulum and the Golgi apparatus, glycerol-3-phosphate dehydrogenase plays a major role in lipid biosynthesis, creatine kinase U-type catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate. Platelet-activating factor acetylhydrolase IB subunit alpha and voltage depedent anion-selective channel protein 2 were also increased. Conclusions : The results suggest that acupuncture stimulation at HT7 may enhance glucose and lipid metabolism, protein synthesis, cytoskeletal substance and anti-oxidative stress in hippocampus.
    01/2012; 29(2).
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