Role of the prion protein in copper turnover in astrocytes

Abstract

The prion protein (PrP(c)) is a glycoprotein that is not only expressed predominantly by neurones but also by other cells, including astrocytes. The recent identification of PrP(c) as a Cu-binding protein has opened the way to investigating its function in a cellular context. Experiments with recombinant PrP showed that the protein could block copper (Cu) toxicity to neurones. This inhibition was due to the protein's Cu-binding capacity. Astrocytes expressing PrP(c) were also able to block Cu toxicity. Analysis of PrP(c) expression by astrocytes showed that the level of extracellular Cu modulates both the level of expression of PrP(c) and its turnover. This in turn modulates the level of Cu stored within astrocytes. Experiments with radioactive Cu suggest that astrocytes may have an important role in uptake and clearance of Cu dependent upon PrP(c) expression. In addition, it was found that astrocytes clear Cu released by neurones. Astrocytes were also shown to take up PrP(c) released from neurones. As PrP(c) is a Cu-binding protein, it is possible that PrP(c) collects Cu from the extracellular environment and shuttles it to astrocytes, where Cu can be stored or exported in proteins such as ceruloplasmin. These results indicate that PrP(c) plays a role in the regulation of Cu taken up by astrocytes and potentially protects neurones from Cu toxicity by this mechanism.