Oxidative impairment in scrapie‐infected mice is associated with brain metals perturbations and altered antioxidant activities

Abstract

Prion diseases are characterized by the conversion of the normal cellular prion protein (PrP C ) into a pathogenic isoform (PrP Sc ). PrP C binds copper, has superoxide dismutase (SOD)-like activity in vitro, and its expression aids in the cellular response to oxidative stress. However, the interplay between PrPs (PrP C , PrP Sc and possibly other abnormal species), copper, anti-oxidation activity and pathogenesis of prion diseases remain unclear. In this study, we reported dramatic depression of SOD-like activity by the af®nity-puri®ed PrPs from scrapie-infected brains, and together with signi®-cant reduction of Cu/Zn-SOD activity, correlates with signi®cant perturbations in the divalent metals contents. We also detected elevated levels of nitric oxide and superoxide in the infected brains, which could be escalating the oxidative modi®cation of cellular proteins, reducing gluathione peroxidase activity and increasing the levels of lipid peroxidation markers. Taken together, our results suggest that brain metal imbalances, especially copper, in scrapie infection is likely to affect the anti-oxidation functions of PrP and SODs, which, together with other cellular dysfunctions, predispose the brains to oxidative impairment and eventual degeneration. To our knowledge, this is the ®rst study documenting a physiological connection between brain metals imbalances, the anti-oxidation function of PrP, and aberrations in the cellular responses to oxidative stress, in scrapie infection.

Prevention of Copper-Induced Calcium Influx and Cell Death by Prion-Derived Peptide in Suspension-Cultured Tobacco Cells

“…Watt et al (2005) suggested that the Cu-bound octarepeat-dependent progress in β-cleavage of PrP C is an early and critical event in the mechanism of protecting cells by PrP acting against the oxidative stress. Furthermore, it was shown that Cu-bound PrP C possesses some superoxide dismutase (SOD)-like activity in vitro, and its expression likely contributes to the cellular response to oxidative damages to cells (Wong et al, 2001). Sauer et al (1999) have proposed that PrP C expression in tumour spheroids is regulated by the internal redox statuses meeting the requirement to protect cells from ROS since they have observed in tumour spheroids that an increase in ROS stimulates the production of PrP C and other ROS-scavenging enzymes such as Cu,Zn-SOD and catalase, while ROS-lowering treatments effectively down-regulate the expression of both ROS-scavenging enzymes and PrP C .…”

Copper-Binding Peptides from Human Prion Protein and Newly Designed Peroxidative Biocatalysts

“…Key involvement of metals (especially copper) in prion diseases has been well documented by a number of works (Watt et al, 2005;Wong et al, 2001;Sauer et al, 1999). However, two opposing roles for copper-bound PrPs have been proposed, namely as anti-oxidants and contrary as pro-oxidants enhancing the neurodegenerative process (Opazo et al, 2003).…”

“…However, two opposing roles for copper-bound PrPs have been proposed, namely as anti-oxidants and contrary as pro-oxidants enhancing the neurodegenerative process (Opazo et al, 2003). The likely factors associated with generation (Kawano, 2007) or removal of ROS (Wong et al, 2001) within PrPs are Cu-binding sequences highly preserved in PrPs.…”

Redox Control of Prion and Disease Pathogenesis

“…The underlying mechanism leading to the development of protein aggregates and accompanying neurotoxicity is relatively clear for some of these conditions, whereas in others, it is still debated. Recent evidence suggests the imbalance of brain metal homeostasis as a common cause of neuronal death in several of these disorders (9,45,48,60,61,70,111,148,171,203,242). It is believed that a redox-active metal interacts with a specific protein and is reduced in its presence, resulting in the generation of reactive oxygen species (ROS), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (OH ) that cause aggregation of the involved protein (16,206,215,224,225).…”