Expression of Prion Protein Increases Cellular Copper Binding and Antioxidant Enzyme Activities but Not Copper Delivery

Rachidi, Walid; Vilette, Didier; Guiraud, Pascal; Arlotto, Marie; Riondel, J; Laude, Hubert; Lehmann, Sylvain; Favier, Alain

doi:10.1074/jbc.m211830200

Cited by 182 publications

(182 citation statements)

References 54 publications

(62 reference statements)

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“…Interestingly, 67 Cu levels in SOD 1 are in direct proportion to PrP C -expression levels, suggesting that decreased SOD 1 activity in PrP C -deficient cells may in part be due to deficient delivery of copper to the enzyme (33). Similar observations have been reported for a rat kidney cell line RK13A, in which expression of PrP C increases copper binding and the activities of antioxidant enzymes without altering copper delivery (180). Although these observations implicate PrP C as a major copper-uptake and -delivery protein, this is unlikely, because the brain copper and zinc content of mice expressing wild-type levels or 10-fold higher levels of PrP C are similar to those in mice lacking PrP (PrP À=À ) (231), leaving the matter unsettled.…”

Section: A Prp and Copper Interactionsupporting

confidence: 72%

Redox Control of Prion and Disease Pathogenesis

Singh

Das

et al. 2010

Antioxidants & Redox Signaling

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Imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals like iron and copper is an important trigger of neurotoxicity in several neurodegenerative conditions, including prion disorders. Whereas some reports attribute this to end-stage disease, others provide evidence for specific mechanisms leading to brain metal dyshomeostasis during disease progression. In prion disorders, imbalance of brain-iron homeostasis is observed before end-stage disease and worsens with disease progression, implicating ironinduced oxidative stress in disease pathogenesis. This is an unexpected observation, because the underlying cause of brain pathology in all prion disorders is PrP-scrapie (PrP Sc ), a b-sheet-rich conformation of a normal glycoprotein, the prion protein (PrP C ). Whether brain-iron dyshomeostasis occurs because of gain of toxic function by PrP Sc or loss of normal function of PrP C remains unclear. In this review, we summarize available evidence suggesting the involvement of oxidative stress in prion-disease pathogenesis. Subsequently, we review the biology of PrP C to highlight its possible role in maintaining brain metal homeostasis during health and the contribution of PrP Sc in inducing brain metal imbalance with disease progression. Finally, we discuss possible therapeutic avenues directed at restoring brain metal homeostasis and alleviating metal-induced oxidative stress in prion disorders. Antioxid. Redox Signal. 12, 1271-1294.

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Section: A Prp and Copper Interactionsupporting

confidence: 72%

Redox Control of Prion and Disease Pathogenesis

Singh

Das

et al. 2010

Antioxidants & Redox Signaling

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“…The ability of PrP C to bind Cu 2ϩ in vivo and in vitro infers PrP may have a physiological role in copper homeostasis (7,9). Copper has been shown to promote the endocytosis of PrP C (33,34), but PrP expression levels do not seem to affect copper delivery (35,36). Copper-induced cleavage of the PrP C main chain has also been reported (37,38) and PrP C can act as an antioxidant by sacrificially quenching hydroxyl radicals produced via Cu 2ϩ /Cu ϩ Fenton's cycling (15).…”

Section: ؉mentioning

confidence: 99%

Deconvoluting the Cu2+ Binding Modes of Full-length Prion Protein

Klewpatinond

Davies

Bowen

et al. 2008

Journal of Biological Chemistry

140

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Sc , is a proteinaceous infectious particle, devoid of nucleic acids, which is responsible for bovine spongiform encephalopathy in cattle and a number of prion diseases in humans, including Creutzfeldt Jakob Disease (1-3). Normal cellular prion protein (PrP C ) is typically 209 residues long, attached to the cell surface by a glycosylphosphatidylinositol anchor. The C-terminal domain between residues 126 and 231 is mainly ␣-helical (4). In contrast, in the absence of copper ions, the N-terminal domain between residues 23 and 125 is unstructured (5) and exhibits a high degree of main chain flexibility (6). It is this natively unfolded domain that includes octarepeat sequences that bind a number of Cu 2ϩ ions (7-9). Metal imbalance is a feature of prion disease (10) and when isolated from diseased brain, PrP Sc has been found to be occupied with metal (11). Metal binding to the prion protein is altered in human prion disease (12), with levels of cellular copper affected by scrapie infection (13) and the ability for disease progression in infected mice to be slowed with the use of copper-specific chelation therapy (14). Copper-catalyzed redox damage of PrP (15) is linked to prion disease (16, 17), although, the copper binding octarepeat region is not required for prion infectivity and propagation (18). Cu 2ϩ binding has also been noted outside the octarepeats, in the so called 5th site (8, 19 -23). This region is an amyloidogenic, neurotoxic segment of PrP that is essential for prion replication (18, 24 -29). Interestingly, the presence, or absence, of Cu 2ϩ ions may also confer different strains of prion disease (11, 30). PrP C is concentrated at presynaptic membranes in the central nervous system, where Cu 2ϩ is also highly localized (32). The ability of PrP C to bind Cu 2ϩ in vivo and in vitro infers PrP may have a physiological role in copper homeostasis (7, 9). Copper has been shown to promote the endocytosis of PrP C (33, 34), but PrP expression levels do not seem to affect copper delivery (35,36). Copper-induced cleavage of the PrP C main chain has also been reported (37,38) (22), and mass spectrometry (30).There have been numerous Cu 2ϩ binding studies of fragments of PrP centered on two regions within the unstructured N-terminal domain of PrP. These studies include the octarepeat region, residues 58 -91, and a second Cu 2ϩ binding region between the octarepeats and the C-terminal structured domain, between residues 90 and 126. Mammalian PrPs contain a repeating motif of 8 amino acids, typically, four octarepeats between residues 60 and 91 with each repeat containing a histidine residue. It is this unstructured, highly conserved * This work was supported in part by Biotechnology and Biological Sciences Research Council Project grants. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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“…For example, deletion of PrP C increased neuronal predisposition to damage by modulating susceptibility to apoptosis 9,10 and the negative consequences of oxidative stress. [11][12][13] Furthermore, in vivo studies demonstrated that PrP C -deficient mice were more prone to seizure induction, 14 and exhibited an increased extent of cerebral damage following an ischemic challenge. 15 In contrast, adenovirus-mediated PrP C overexpression reduced CNS damage in a rat model of cerebral ischemia.…”

mentioning

confidence: 99%