Metal imbalance and compromised antioxidant function are early changes in prion disease

Abstract

The prion protein (PrP) has been shown to bind copper. In the present study we have investigated whether prion disease in a mouse scrapie model resulted in modification of metal concentrations. We found changes in the levels of copper and manganese in the brains of scrapie-infected mice prior to the onset of clinical symptoms. Interestingly, we noted a major increase in blood manganese in the early stages of disease. Analysis of purified PrP from the brains of scrapie-infected mice also showed a reduction in copper binding to the protein and a proportional decrease in antioxidant activity between 30 and 60 days post-inoculation. We postulate that alterations in trace-element metabolism as a result of changes in metal binding to PrP are central to the pathological modifications in prion disease.

Manganese-induced changes of the biochemical characteristics of the recombinant wild-type and mutant PrPs

“…It has been widely documented that conversion of the native, predominant -helical conformation of PrP C into the pathological, -stranded conformation of PrP Sc is the critical step for the propagation of prion during the TSE pathogenicity. Numerous macro-and micro-molecular agents have been addressed to involve in this process, which seem to favor or inhibit the PrP conversion process [17]. Our data supply the molecular evidence that manganese might work as a cofactor to favor the conversion of PrP C into PrP Sc .…”

“…Disturbances in the levels of manganese and copper have been observed in the brain tissues of some kinds of prion diseases [17,18]. In the present study, reliable molecular evidences of the inXuences of manganese on the main biochemical and structural features of the recombinant PrPs have been proposed.…”

Scavenger, transducer, RNA chaperone? What ligands of the prion protein teach us about its function

“…Furthermore, occupancy of the protein by distinct metal ions was also shown to determine strain-specific conformations of PrP Sc [32,33]. These data, combined to the observation of an altered metal-ion metabolism in the course of the disease [33,44], suggest that metalion occupancy of PrP plays a central role in both the pathogenesis and phenotypic diversity of prion diseases. However, the hypothesis that was once proposed, of a link between scrapie incidence and the levels of trace elements in soil was refuted by a careful analysis, which failed to evidence any such correlation [45].…”

“…The observation that PrP binds cooperatively to copper ions within their physiological range of concentration suggests that it could play a specialized function in the metabolism of copper and other metal ions. This is also supported by the changes in metal balance that were observed in tissues from diseased animals or from patients with Creutzfeldt-Jakob disease [33,44,48]. Since it is primarily expressed in the central nervous system (CNS), PrP C has been proposed to act in copper or zinc homeostasis in that tissue [49].…”

The intriguing prion disorders

“…A role in normal brain copper metabolism is suggested by the finding that the octapeptide repeats of PrP C are able to bind copper within the physiological concentration range [53,54]. In animal models, significant changes have been detected in the levels of brain copper in scrapie-infected mice, before the onset of clinical symptoms [55,56]. Furthermore, in human sporadic CJD there is a decrease of up to 50% in brain copper levels [56].…”