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Role of PrP in uptake and release of metal ions 1

Using neuronal cells expressing PrP and mutants with deletions or insertions in the octapeptide repeats we have been investigating the role of PrP in the uptake and cellular metabolism of copper and zinc ions. Aspects of this work have been in collaboration with Dr Alan Favier's group (Partner 4) using radioactive metal ions (64Cu, 65Zn ) to examine the role of PrP in the uptake of metal ions by cells. In an alternative strategy we have initiated studies using the zinc binding fluorophore Zinpyr to determine whether PrP has a role to play in the cellular uptake of zinc.

Although copper promotes the endocytosis of PrP from the cell surface, at lower concentrations we noticed that it promoted the shedding of PrP. Whilst the expression of PrP was unaltered by copper treatment, the level of PrP in the conditioned media was increased 2-fold at a copper concentration of 1.5uM. The amount of shed PrP continued to increase until a peak was reached at 5 uM copper after which levels began to decrease again but remained above control levels. Copper-induced shedding of PrP into the medium was almost abolished by co-incubation with an hydroxamate inhibitor indicating the involvement of a zinc-metalloprotease in the copper-induced shedding of PrP.

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