Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis

Greene, Jennifer C.; Whitworth, Alexander J.; Andrews, Laurie A.; Parker, Tracey J.; Pallanck, Leo J.

doi:10.1093/hmg/ddi074

Cited by 182 publications

(140 citation statements)

References 79 publications

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“…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: 87%

“…In an effort to identify pathways that influence the Drosophila parkin phenotypes, we performed a genetic screen for dominant modifiers of a parkin partial pupal lethal phenotype, which appears to result from muscle dysfunction (15). A loss-offunction allele of GstS1 was the strongest enhancer recovered from this screen.…”

Section: Resultsmentioning

confidence: 99%

“…We show that parkin is required cell-autonomously to prevent degeneration of a subset of DA neurons in the brain. The neurodegenerative phenotype of parkin mutants is enhanced by a loss-of-function allele of the glutathione S-transferase S1 (GstS1) gene that was identified in a screen for modifiers of a parkin partial lethal phenotype (15). Furthermore, we demonstrate that overexpression of GstS1 prevented DA neuron degeneration in parkin mutants.…”

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confidence: 78%

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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.

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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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Section: Discussionmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 78%

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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.

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388

373

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“…S2 cells in a 24-well plate were transfected with a pMT plasmid (Invitrogen) encoding a mitochondrially targeted PAGFP (47) and then treated with 2 g of the appropriate double stranded RNA for 3-4 days as described in ref. 31. Further details provided in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

The PINK1/Parkin pathway regulates mitochondrial morphology

Poole

Thomas

Andrews

et al. 2008

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

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664

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Loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) or parkin genes, which encode a mitochondrially localized serine/ threonine kinase and a ubiquitin-protein ligase, respectively, result in recessive familial forms of Parkinsonism. Genetic studies in Drosophila indicate that PINK1 acts upstream of Parkin in a common pathway that influences mitochondrial integrity in a subset of tissues, including flight muscle and dopaminergic neurons. The mechanism by which PINK1 and Parkin influence mitochondrial integrity is currently unknown, although mutations in the PINK1 and parkin genes result in enlarged or swollen mitochondria, suggesting a possible regulatory role for the PINK1/Parkin pathway in mitochondrial morphology. To address this hypothesis, we examined the influence of genetic alterations affecting the machinery that governs mitochondrial morphology on the PINK1 and parkin mutant phenotypes. We report that heterozygous loss-offunction mutations of drp1, which encodes a key mitochondrial fission-promoting component, are largely lethal in a PINK1 or parkin mutant background. Conversely, the flight muscle degeneration and mitochondrial morphological alterations that result from mutations in PINK1 and parkin are strongly suppressed by increased drp1 gene dosage and by heterozygous loss-of-function mutations affecting the mitochondrial fusion-promoting factors OPA1 and Mfn2. Finally, we find that an eye phenotype associated with increased PINK1/Parkin pathway activity is suppressed by perturbations that reduce mitochondrial fission and enhanced by perturbations that reduce mitochondrial fusion. Our studies suggest that the PINK1/Parkin pathway promotes mitochondrial fission and that the loss of mitochondrial and tissue integrity in PINK1 and parkin mutants derives from reduced mitochondrial fission.caused by the degeneration of dopaminergic neurons in the midbrain. The molecular mechanisms underlying neurodegeneration in PD remain unclear, although substantial evidence suggests that mitochondrial dysfunction is a major contributor: Several mitochondrial toxins induce PD-like symptoms in humans and animal models (1, 2); systemic mitochondrial dysfunction appears to be a feature of a large proportion of PD sufferers (3); and several genes involved in rare heritable forms of Parkinsonism have been implicated in mitochondrial biology, including the PTEN-induced kinase 1 (PINK1) and parkin genes (4, 5).The PINK1 and parkin genes encode a mitochondrially localized serine/threonine kinase and an E3 ubiquitin-protein ligase, respectively (6-13). Although a number of substrates of PINK1 and Parkin have been described, these advances have led to dramatically varying models of pathogenesis (5,(14)(15)(16)(17)(18)(19), making it unclear precisely how PINK1 and Parkin influence neuronal integrity. Genetic studies of highly conserved Drosophila orthologs of parkin and PINK1 indicate that PINK1 acts upstream of Parkin in a common pathway that influences the integrity of flight muscle, sperm, and a subset of dopaminer...

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“…Parkin mutant flies present with male and female sterility (Riparbelli and Callaini, 2007), mitochondrial and muscle abnormalities, locomotor defects, an inability to fly owing to degeneration of indirect flight muscles, increased sensitivity to multiple stresses, including oxidative stress, and a severely reduced lifespan (Palacino et al, 2004;Greene et al, 2005;Whitworth et al, 2005). Some of these defects arise because parkin mutants have dysfunctional mitochondria with disturbances in the electron transport chain.…”

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confidence: 99%

Zinc supplement greatly improves the condition of parkin mutant Drosophila

Saini

Schaffner

2010

Biological Chemistry

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Parkinson's disease (PD) is a progressive neurodegenerative disorder in which oxidative stress is implicated as a major causative factor. Mutations in the gene encoding Parkin, a ubiquitin ligase, are responsible for a familial form of PD. In a Drosophila disease model lacking Parkin (park 25 null mutant), we tested the effect of zinc supplementation. Zinc is an essential trace metal and a component of many enzymes and transcriptional regulators. Unlike copper and iron, zinc is not redox-active and under most conditions serves as an antioxidant. We find that the condition of parkin mutants raised on zinc-supplemented food is greatly improved. At zinc concentrations where controls begin to show adverse effects as a result of the metal supplement, parkin mutants perform best, as manifested in a higher frequency of reaching adulthood, extended lifespan and improved motoric abilities.

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Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis

Cited by 182 publications

References 79 publications

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

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

The PINK1/Parkin pathway regulates mitochondrial morphology

Zinc supplement greatly improves the condition of parkin mutant Drosophila

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