Prion Protein-Deficient Neurons Reveal Lower Glutathione Reductase Activity and Increased Susceptibility to Hydrogen Peroxide Toxicity

White, Anthony R.; Collins, Steven J.; Maher, Frances A.; Jobling, Michael F.; Stewart, Leanne R.; Thyer, James M.; Beyreuther, Konrad; Masters, Colin L.; Cappai, Roberto

doi:10.1016/s0002-9440(10)65487-9

Cited by 181 publications

(115 citation statements)

References 54 publications

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“…The activity of antioxidant enzymes, such as glutathione peroxidase and superoxide dismutase, is altered in PrP C null mice and in scrapie-infected brains (48,49). These findings suggest that PrP C participates in the modulation of the activity of these enzymes and/or PrP C itself functions as an antioxidant molecule.…”

Section: Discussionmentioning

confidence: 99%

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

Lee

Raymond

Schoen

et al. 2007

Journal of Biological Chemistry

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Hemin (iron protoporphyrin IX) is a crucial component of many physiological processes acting either as a prosthetic group or as an intracellular messenger. Some unnatural, synthetic porphyrins have potent anti-scrapie activity and can interact with normal prion protein (PrP C ). These observations raised the possibility that hemin, as a natural porphyrin, is a physiological ligand for PrP C . Accordingly, we evaluated PrP C interactions with hemin. When hemin (3-10 M) was added to the medium of cultured cells, clusters of PrP C formed on the cell surface, and the detergent solubility of PrP C decreased. The addition of hemin also induced PrP C internalization and turnover. The ability of hemin to bind directly to PrP C was demonstrated by hemin-agarose affinity chromatography and UV-visible spectroscopy. Multiple hemin molecules bound primarily to the N-terminal third of PrP C , with reduced binding to PrP C lacking residues 34 -94. These hemin-PrP C interactions suggest that PrP C may participate in hemin homeostasis, sensing, and/or uptake and that hemin might affect PrP C functions.

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Section: Discussionmentioning

confidence: 99%

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

Lee

Raymond

Schoen

et al. 2007

Journal of Biological Chemistry

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“…Studies in vivo, on the brains of PrP-null mouse lines, and in vitro, on primary neuronal cultures derived from these lines, have revealed a reduction in the activities of the antioxidant enzymes SOD1 and glutathione reductase in the absence of PrP. 46,47 Additionally, cultured PrP-deficient neurons were found to have increased susceptibility to hydrogen peroxide or oxygenfree radical toxicity. Furthermore, we have found evidence of oxidative stress-induced damage in the form of increased levels of protein oxidation and lipid peroxidation in the brains of the Dpl-expressing ataxic, Rcm0, line as compared with the nonataxic, Npu, line.…”

Section: Discussionmentioning

confidence: 99%

Male Infertility and DNA Damage in Doppel Knockout and Prion Protein/Doppel Double-Knockout Mice

Paisley

Banks

Selfridge

et al. 2004

The American Journal of Pathology

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The prion protein (PrP) and Doppel (Dpl) have many structural and biochemical properties in common, leading to the suggestion that the lack of an obvious phenotype in PrP-deficient mice maybe because of compensation by Dpl. To test this hypothesis and also investigate the function of Dpl we have generated Prnd ؊/؊ and Prnp ؊/؊ /Prnd ؊/؊ mouse lines. Both develop normally and display an identical male sterility phenotype that differs from that reported for another Prnd ؊/؊ mouse line. Sperm from both our mutant lines were present at normal concentrations, had normal motility, and no morphological abnormalities. Despite only rarely fertilizing oocytes in vivo, because of an inability to perform the acrosome reaction, mutant sperm were capable of fertilization in vitro, albeit at reduced rates compared to wild type. Elevated levels of oxidative DNA damage were found in both types of mutant sperm and resulting embryos failed at an early stage. Therefore we found no evidence that Dpl compensates for the loss of PrP function in mutant mouse lines, but it does have an important anti-oxidant function necessary for sperm integrity and male fertility.

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“…ROS, such as the superoxide radical (O 2 . ) and hydrogen peroxide (H 2 O 2 ), which although itself not an ROS is an important mediator of oxidative stress in neurons (20), can oxidatively modify biomolecules (21). The generation of such ROS is promoted by the presence of copper and iron through the Fenton reaction (22).…”

mentioning

confidence: 99%

Cleavage of the Amino Terminus of the Prion Protein by Reactive Oxygen Species

McMahon¹,

Mangé²,

Nishida³

et al. 2001

Journal of Biological Chemistry

145

149

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Prion Protein-Deficient Neurons Reveal Lower Glutathione Reductase Activity and Increased Susceptibility to Hydrogen Peroxide Toxicity

Abstract: The prion protein (PrP) has a central role in the pathogenesis of transmissible spongiform encephalopathies (TSE).Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy (TSE) with some variants (nvCJD) zoonotically linked to bovine spongiform encephalopathy.

Cited by 181 publications

References 54 publications

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

Male Infertility and DNA Damage in Doppel Knockout and Prion Protein/Doppel Double-Knockout Mice

Cleavage of the Amino Terminus of the Prion Protein by Reactive Oxygen Species

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