Phenotypic rescue by a bovine transgene in a Cu/Zn superoxide dismutase-null mutant of Drosophila melanogaster.

Reveillaud, Isabelle; Phillips, J. P.; Duyf, B; Hilliker, Arthur J.; Kongpachith, Ana; Fleming, James E.

doi:10.1128/mcb.14.2.1302

Cited by 37 publications

(16 citation statements)

References 24 publications

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“…In C. elegans , Doonan et al [67], Yang et al [68], Yen et al [69], and Van Raamsdonk et al [70] demonstrated that the absence of SOD genes (both the cytosolic and mitochondrial isoforms) had no effect on lifespan, either in WT or in long-lived mutants despite the fact that these genetic manipulations increased both the sensitivity of the nematodes to oxidative stress (paraquat) and levels of oxidative damage to proteins. Drosophila lacking either CuZnSOD ( SOD1 ) or MnSOD ( SOD2 ) show a severe phenotype, e.g., deletion in CuZnSOD resulted in 80% reduction in lifespan [71, 72]; deletion in Sod2 induced postnatal lethality [73, 74]; Drosophila heterozygous for the SOD1 gene show no significant differences, and SOD2 gene show a slight reduction in lifespan [71, 74, 75]. …”

Section: Discussionmentioning

confidence: 99%

“…The lifespan (clonal and chronological) of yeast has been reported to be increased by the overexpression of MsrA [66] and MsrB [66], and MnSOD [65, 87]. Initial studies in Drosophila using P-element mediated transformation reported that overexpressing either CuZnSOD [72, 88, 89] or catalase [90] had no effect on lifespan. Later, Orr and Sohal [89] reported that overexpression of both CuZnSOD and catalase significantly increased the lifespan of Drosophila .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Is the oxidative stress theory of aging dead?

Pérez¹,

Bokov²,

Remmen³

et al. 2009

Biochimica et Biophysica Acta (BBA) - General Subjects

524

406

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Currently, the Oxidative Stress (or Free Radical) Theory of Aging is the most popular explanation of how aging occurs at the molecular level. While data from studies in invertebrates (e.g., C. elegans and Drosophila) and rodents show a correlation between increased lifespan and resistance to oxidative stress (and in some cases reduced oxidative damage to macromolecules), direct evidence showing that alterations in oxidative damage/stress play a role in aging are limited to a few studies with transgenic Drosophila that overexpress antioxidant enzymes. Over the past eight years, our laboratory has conducted an exhaustive study on the effect of under- or overexpressing a large number and wide variety of genes coding for antioxidant enzymes. In this review, we present the survival data from these studies together. Because only one (the deletion of the Sod1 gene) of the 18 genetic manipulations we studied had an effect on lifespan, our data calls into serious question the hypothesis that alterations in oxidative damage/stress play a role in the longevity of mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Is the oxidative stress theory of aging dead?

Pérez¹,

Bokov²,

Remmen³

et al. 2009

Biochimica et Biophysica Acta (BBA) - General Subjects

524

406

View full text Add to dashboard Cite

show abstract

“…Overt symptoms of the SOD-null syndrome have been described only in homozygotes and are ameliorated by P element-vectored SOD transgenes (ref. 17; T. Parkes, A.J.H., and J.P.P., unpublished data).…”

mentioning

confidence: 83%

Subunit-destabilizing mutations in Drosophila copper/zinc superoxide dismutase: neuropathology and a model of dimer dysequilibrium.

Phillips

Tainer

Getzoff

et al. 1995

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

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Mutations in Cu/Zn superoxide dismutase (SOD), a hallmark of familial amyotrophic lateral sclerosis (FALS) in humans, are shown here to confer striking neuropathology in Drosophila. Heterozygotes with one wild-type and one deleted SOD allele retain the expected 50Y% of normal activity for this dimeric enzyme. However, heterozygotes with one wild-type and one missense SOD allele show lesser SOD activities, ranging from 37% for a heterozygote carrying a missense mutation predicted from structural models to destabilize the dimer interface, to an average of 13% for several heterozygotes carrying missense mutations predicted to destabilize the subunit fold. Genetic and biochemical evidence suggests a model of dimer dysequilibrium whereby SOD activity in missense heterozygotes is reduced through entrapment of wild-type subunits into unstable or enzymatically inactive heterodimers. This dramatic impairment of the activity ofwild-type subunits in vivo has implications for our understanding of FALS and for possible therapeutic strategies.Mutations in Cu/Zn superoxide dismutase (SOD, EC 1.15.1.1) have been identified in the etiology of familial amyotrophic lateral sclerosis (FALS), a syndrome commonly known as Lou Gehrig's disease (1, 2). Some FALS-affected individuals are carriers of missense mutations that appear to alter the stability (3) and/or the function of this critical oxygen radicalmetabolizing enzyme (2). The dominant phenotype associated with FALS mutations in SOD could result from loss of enzyme function, consistent with the reduced SOD activity in FALS patients (2, 4-7), or from the gain of a deleterious function, such as enhanced reactivity with peroxynitrite leading to elevated protein-tyrosine nitration (8, 9), consistent with the motor neuron damage found in transgenic mice overexpressing FALS-type mutant SOD (10, 11).A direct test of the relationship between SOD subunit function and neurodegenerative disease would be to induce and select mutations in SOD in an organism amenable to genetic analysis and then characterize the biochemical and neurological consequences conferred by these mutations. We have previously shown that null mutation for SOD in Drosophila melanogaster confers a syndrome including reduced adult lifespan, infertility, toxic hypersensitivity to a variety of oxygen stress conditions, and lethality in combination with mutations conferring defects in other oxygen radical scavengers (12-16). Overt symptoms of the SOD-null syndrome have been described only in homozygotes and are ameliorated by P element-vectored SOD transgenes (ref. 17; T. Parkes, A.J.H., and J.P.P., unpublished data).Here we show that mutations in SOD in Drosophila, as in humans, cause neuropathology. We also show that missense mutations expected to destabilize SOD subunits and dimer assembly significantly impair the activity of normal subunits in heterozygotes for a wild-type allele, resulting in significantly lower enzyme activity than expected in heterozygotes. These findings are important to our understanding of...

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“…Treatment of C. elegans with superoxide dismutase mimetics has been reported to extend their lifespan [56], but these experiments have yet to be successfully repeated in other laboratories [57,58]. In the fruit fly Drosophila melanogaster , the absence of CuZn superoxide dismutase diminishes lifespan by ~80% and increases sensitivity to oxidative stress, whereas flies with one-half the normal amount of this enzyme have a normal lifespan [59,60]. Flies lacking Mn superoxide dismutase do not develop to adulthood, but those with only 50% reduction of this enzyme are slightly shorter-lived than control [61,62].…”

Section: Introductionmentioning

confidence: 99%

Update on the oxidative stress theory of aging: Does oxidative stress play a role in aging or healthy aging?

Salmon

Richardson

Pérez

2010

Free Radical Biology and Medicine

385

303

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The oxidative stress theory of aging predicts that manipulations that alter oxidative stress/damage will alter aging. The gold standard for determining whether aging is altered is lifespan, i.e., does altering oxidative stress/damage change lifespan? Mice with genetic manipulations in the antioxidant defense system designed to directly address this prediction have, with few exceptions, shown no change in lifespan. However, when these transgenic/knockout mice are tested using models that develop various types of age-related pathology, they show alterations in progression and/or severity of pathology as predicted by the oxidative stress theory; increased oxidative stress accelerates pathology and reduced oxidative stress retards pathology. These contradictory observations might mean a) oxidative stress plays a very limited, if any, role in aging but a major role in healthspan; and/or b) the role that oxidative stress plays in aging depends on environment. In environments with minimal stress, as expected under optimal husbandry, oxidative damage plays little role in aging. However, under chronic stress, including pathological phenotypes that diminish optimal health, oxidative stress/damage plays a major role in aging. Under these conditions, enhanced antioxidant defenses exert an “anti-aging” action, leading to changes in lifespan, age-related pathology, and physiological function as predicted by the oxidative stress theory of aging.

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Phenotypic rescue by a bovine transgene in a Cu/Zn superoxide dismutase-null mutant of Drosophila melanogaster.

Abstract: Null mutants for Cu/Zn superoxide dismutase (CuZnSOD)

Cited by 37 publications

References 24 publications

Is the oxidative stress theory of aging dead?

Is the oxidative stress theory of aging dead?

Subunit-destabilizing mutations in Drosophila copper/zinc superoxide dismutase: neuropathology and a model of dimer dysequilibrium.

Update on the oxidative stress theory of aging: Does oxidative stress play a role in aging or healthy aging?

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