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

Role of PrP as a metallochaperone

Two strategies were used to investigate the possible role of PrP as a metallochaperone:
- study of the inntracellular trafficking of the prion protein under metal ions, and
- the relationshipe between the prion protein and two others metalloproteins.

Transition metal ions treatment of unstimulated and doxo-stimulated A74 cells revealed a decrease in PrPC expression outer of the cell, which is more visible with copper or zinc compared to the manganese. The modulation of expression and distribution of the PrPC by transition metal ions remain intriguing since the protein was suggest to bind not only copper but also zinc, and manganese. Immunostaining analysis of permeabilised cells indicates that intracellular accumulation of the PrPC in A74 cells was a result of an internalisation event of the protein mediated by transition metal ions specially copper and zinc, this observation is corroborated also by the surface biotinylation which reveal an endocytosis of the PrPC. The lack of manganese mediated internalisation may be due to its low affinity for the prion protein.

Laser confocal analysis indicates that the trans-Golgi compartment represent the major intracellular site in which PrPC accumulates in copper exposed cells. These data indicate that mediated PrPC internalisation is metal ions type dependent, which is controlled by the metal ions binding affinity to PrPC. This study reveals also that transition metal ions, specially copper ions do not mediate only the internalisation of the prion protein but also promote its intracellular accumulation and its N-terminal cleavage in A74 cells. Indeed, exposition of Dox-stimulated A74 to metal ions generate a 17 -kDa polypeptide, which corresponding to the N-terminal region of the prion protein. The role of metal ion, especially the copper ion in the trafficking of this protein, on the PrPC to PrPsc conversion process and in the physiopathological of the prion diseases is still in controversy.

Metallochaperone activity may involve the cooperation of several metalloproteins. Thus, we have pointed our effort to establish the relationship between the prionprotein and others coproprotein including metallothionein and ceruloplasmin. Expression of both metallothionein and ceruloplasmin is increased in PrP over-expressing cells which suggests that PrP either act as a metallochaprone delivering copper or more likely is involved in a signalling cascade inducing expression of other metallochaprones.

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LAN, UNIVERSITE JOSEPH FOURIER - GRENOBLE 1
17 Avenue des Martyrs
38054 Grenoble
France
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