Effect of Wild-type or Mutant Parkin on Oxidative Damage, Nitric Oxide, Antioxidant Defenses, and the Proteasome

Hyun, Dong Hoon; Lee, Moon Hee; Hattori, Nobutaka; Kubo, S.; Mizuno, Yoshikuni; Halliwell, Barry; Jenner, Peter

doi:10.1074/jbc.m200666200

Cited by 163 publications

(115 citation statements)

References 61 publications

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“…Of these five genes, ␣-Syn, parkin, and DJ-1 have been most intensively studied. Studies using in vivo animal models and in vitro cell culture have linked mutations of these genes to impairments of mitochondrial structure and function and oxidative stress response, reinforcing the general involvement of mitochondrial dysfunction and oxidative stress in PD pathogenesis (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Consistent with this notion, these proteins have been shown to be present in mitochondria or interact with mitochondrial proteins (8,(22)(23)(24), suggesting that they may directly regulate mitochondria function.…”

supporting

confidence: 56%

Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin

Yang

Gehrke²,

Imai³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

723

724

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Mutations in Pink1, a gene encoding a Ser͞Thr kinase with a mitochondrial-targeting signal, are associated with Parkinson's disease (PD), the most common movement disorder characterized by selective loss of dopaminergic neurons. The mechanism by which loss of Pink1 leads to neurodegeneration is not understood. Here we show that inhibition of Drosophila Pink1 (dPink1) function results in energy depletion, shortened lifespan, and degeneration of select indirect flight muscles and dopaminergic neurons. The muscle pathology was preceded by mitochondrial enlargement and disintegration. These phenotypes could be rescued by the wild type but not the pathogenic C-terminal deleted form of human Pink1 (hPink1). The muscle and dopaminergic phenotypes associated with dPink1 inactivation show similarity to that seen in parkin mutant flies and could be suppressed by the overexpression of Parkin but not DJ-1. Consistent with the genetic rescue results, we find that, in dPink1 RNA interference (RNAi) animals, the level of Parkin protein is significantly reduced. Together, these results implicate Pink1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in Drosophila.mitochondria ͉ Parkinson's disease ͉ Pten-induced kinase 1 ͉ indirect flight muscle P arkinson's disease (PD) is the most common movement disorder characterized pathologically by the deficiency of brain dopamine content and the selective degeneration of dopaminergic neurons in the substantia nigra. The most common forms of PD are sporadic with no known cause. Nevertheless, postmortem studies have identified common features associated with sporadic PD, such as mitochondrial complex I dysfunction, oxidative stress, and aggregation of abnormal proteins (1, 2).Although initial studies on the etiology of PD have focused on environmental factors, recent genetic studies have firmly established the contribution of inheritable factors in PD pathogenesis (2, 3). At least ten distinct loci have been associated with rare familial forms of PD (FPD). It is anticipated that understanding the molecular lesions associated with these FPD genes will shed light on the pathogenesis of the more common forms of the disease. Dominant mutations in ␣-Synuclein (␣-Syn) and LRRK2͞dardarin and recessive mutations in parkin, DJ-1, and Pink1 have been associated with FPD (4-10). Of these five genes, ␣-Syn, parkin, and DJ-1 have been most intensively studied. Studies using in vivo animal models and in vitro cell culture have linked mutations of these genes to impairments of mitochondrial structure and function and oxidative stress response, reinforcing the general involvement of mitochondrial dysfunction and oxidative stress in PD pathogenesis (11-21). Consistent with this notion, these proteins have been shown to be present in mitochondria or interact with mitochondrial proteins (8,(22)(23)(24), suggesting that they may directly regulate mitochondria function.A further link between mitochondria and PD was supported by the fact that Pink1 encodes a predicted Se...

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supporting

confidence: 56%

Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin

Yang

Gehrke²,

Imai³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

723

724

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“…Our finding that altered GstS1 activity inf luences the parkin mutant phenotypes raises the possibility that parkin may also offer protection from the effects of oxidative stress. Further support for this hypothesis comes from the findings that oxidative damage in f lies, mice, and cell lines and sensitivity to oxidative stress agents in f lies and cell lines correlates inversely with parkin activity (19,(32)(33)(34). Our recent results from transcriptional profiling of parkin mutants and a genetic screen for parkin modifiers also demonstrate that oxidative stress response elements are up-regulated and that mutations in oxidative stress response components enhance the parkin mutant phenotypes (15).…”

Section: Discussionmentioning

confidence: 53%

Increased glutathione S -transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease

Whitworth

Theodore²,

Greene

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

384

373

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Loss-of-function mutations of the parkin gene are a major cause of early-onset parkinsonism. To explore the mechanism by which loss of parkin function results in neurodegeneration, we are using a genetic approach in Drosophila. Here, we show that Drosophila parkin mutants display degeneration of a subset of dopaminergic (DA) neurons in the brain. The neurodegenerative phenotype of parkin mutants is enhanced by loss-of-function mutations of the glutathione S-transferase S1 (GstS1) gene, which were identified in an unbiased genetic screen for genes that modify parkin phenotypes. Furthermore, overexpression of GstS1 in DA neurons suppresses neurodegeneration in parkin mutants. Given the previous evidence for altered glutathione metabolism and oxidative stress in sporadic Parkinson's disease (PD), these data suggest that the mechanism of DA neuron loss in Drosophila parkin mutants is similar to the mechanisms underlying sporadic PD. Moreover, these findings identify a potential therapeutic approach in treating PD.genetic modifier ͉ neurodegeneration ͉ parkin P arkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and the accumulation of proteinaceous intraneuronal inclusions known as Lewy bodies. The mechanisms responsible for neurodegeneration in PD are largely unknown, although previous work suggests that mitochondrial complex I dysfunction, oxidative stress, and aberrant proteolytic degradation may contribute to pathogenesis (1). The recent identification of genes responsible for rare inherited forms of parkinsonism presents an opportunity to establish neurodegenerative mechanisms that may be relevant to sporadic forms of PD.Loss-of-function mutations of parkin are a common cause of autosomal recessive juvenile parkinsonism (ARJP), and parkin dysfunction may also contribute to late-onset sporadic PD (2-6). Patients with parkin mutations display many of the typical features of idiopathic PD, including locomotor dysfunction, reduced mitochondrial complex I activity, and degeneration of DA neurons in the substantia nigra. However, most ARJP cases have a significantly earlier age of onset and lack Lewy body pathology. Parkin has been shown to possess ubiquitin-protein ligase activity (7-9), which acts to confer substrate target specificity in the ubiquitin͞proteasome protein degradation pathway. This finding has led to the model that toxic accumulation of parkin substrates may be responsible for DA neuron death. A number of putative substrates of parkin have been identified (10). Several of these parkin substrates, including the Lewy body component ␣-synuclein (11) and the putative G protein-coupled receptor Pael-R (12), have received considerable attention, in part because they implicate specific cellular pathways in parkinmediated pathogenesis. However, the involvement of many of the identified parkin substrates in the etiology of ARJP remains controversial.To identify pathways relevant to parkin pathogenesis, we are using a gen...

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“…It has been suggested that the presence of mutant Parkin, a multiprotein E3 ubiquitin ligase complex, which in turn is part of the ubiquitin-proteasome system which mediates the targeting of proteins for degradation, increases oxidative stress and sensitizes cells to death induced by different insults. 27 Recent publications have shown a direct link between Parkin and mitochondria. Parkin is specifically recruited to impaired mitochondria and activates the process of mitophagy.…”

Section: Discussionmentioning

confidence: 99%

Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and -independent apoptosis by stimulating ROS formation

et al. 2012

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Autophagy is a catabolic process involved in the turnover of organelles and macromolecules which, depending on conditions, may lead to cell death or preserve cell survival. We found that some lung cancer cell lines and tumor samples are characterized by increased levels of lipidated LC3. Inhibition of autophagy sensitized non-small cell lung carcinoma (NSCLC) cells to cisplatin-induced apoptosis; however, such response was attenuated in cells treated with etoposide. Inhibition of autophagy stimulated ROS formation and treatment with cisplatin had a synergistic effect on ROS accumulation. Using genetically encoded hydrogen peroxide probes directed to intracellular compartments we found that autophagy inhibition facilitated formation of hydrogen peroxide in the cytosol and mitochondria of cisplatin-treated cells. The enhancement of cell death under conditions of inhibited autophagy was partially dependent on caspases, however, antioxidant NAC or hydroxyl radical scavengers, but not the scavengers of superoxide or a MnSOD mimetic, reduced the release of cytochrome c and abolished the sensitization of the cells to cisplatin-induced apoptosis. Such inhibition of ROS prevented the processing and release of AIF (apoptosis-inducing factor) and HTRA2 from mitochondria. Furthermore, suppression of autophagy in NSCLC cells with active basal autophagy reduced their proliferation without significant effect on the cell-cycle distribution. Inhibition of cell proliferation delayed accumulation of cells in the S phase upon treatment with etoposide that could attenuate the execution stage of etoposide-induced apoptosis. These findings suggest that autophagy suppression leads to inhibition of NSCLC cell proliferation and sensitizes them to cisplatininduced caspase-dependent and -independent apoptosis by stimulation of ROS formation.

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Effect of Wild-type or Mutant Parkin on Oxidative Damage, Nitric Oxide, Antioxidant Defenses, and the Proteasome

Cited by 163 publications

References 61 publications

Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin

Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin

Increased glutathione S -transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease

Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and -independent apoptosis by stimulating ROS formation

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