Role of the prion protein in copper turnover in astrocytes

The prion protein (PrPc) is a glycoprotein that is not only expressed predominantly by neurones but also by other cells, including astrocytes. The recent identification of PrPc 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 PrPc were also able to block Cu toxicity. Analysis of PrPc expression by astrocytes showed that the level of extracellular Cu modulates both the level of expression of PrPc 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 PrPc expression. In addition, it was found that astrocytes clear Cu released by neurones. Astrocytes were also shown to take up PrPc released from neurones. As PrPc is a Cu-binding protein, it is possible that PrPc 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 PrPc plays a role in the regulation of Cu taken up by astrocytes and potentially protects neurones from Cu toxicity by this mechanism. (C) 2004 Elsevier Inc. All rights reserved.