Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS

Role of PrP in uptake and release of metal ions 4

In collaboration with Partner 4 and 6 we investigated the role of PrP in the uptake and cellular metabolism of copper and zinc ions. Using neuronal cells expressing PrP and mutants with deletions or insertions in the octapeptide repeats, we used 64Cu, 65Zn and the zinc binding fluorophore Zinpyr to determine whether PrP has a role to play in the binding and uptake of metal ions by cells.

We reported a link between PrPC expression, copper binding at physiological concentration, and resistance to oxidative stress. We used in particular a cell line expressing a doxycycline-inducible murine PrPC gene and our result indicated that PrPC expression did not lead to copper delivery inside the cells. However expression of the protein increased several antioxidant enzyme activities, glutathione levels and resistance to various oxidative insults. Taken together our result suggest that PrP may be a stress sensor sensitive to copper and able to initiate, following copper binding, a signal transduction process acting on the antioxidant systems to improve cell defences.

We also looked more carefully at the effect of zinc. As detailed by partner 4, this metal ion modifies PrP trafficking but there is no clear uptake of Zinc by PrP. However a modification of exchangeable Zinc linked to the differential expression of PrP was observed.

In conclusion PrP seems not directly involved in metal ions uptake but could contribute to it through is binding capacity for metal ions.

Ref: Rachidi W, Vilette D. Guiraud P., Arlotto M, Riondel J, Laude H, Lehmann S & Favier A (2003) Over expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper transport J. Biol. Chem. 278:9064-9072.

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