Role of copper and manganese in prion disease progression

Abstract The cellular prion protein (PrPC ), a copper binding protein has a primary role in the pathogenesis of in prion diseases. In these diseases alterations in the levels of copper and manganese have been described but how these alterations are involved in the pathogenesis is still unknown. Here we analysed synaptosomes of scrapie infected mice and observed a significant reduction in the amount of copper and an increase of the manganese content at day 100 after infection. Moreover a reduction of the copper content in mouse brains induced by application of copper poor diets was found to reduce the survival time of scrapie infected mice significantly, whereas enhanced administration of copper induced a significant delay in prion disease onset. Interestingly a significant higher amount of PrPC full length and misfolded PK-resistant PrP was observed in mice that were treated with an enhanced copper diet compared to controls. Moreover we could demonstrate that in healthy mock infected mice, a Cu2+ rich/Mn2+ poor diet induced a significantly decreased cleavage capability of PrPC compared to control mice. These new findings suggest that the copper content in mouse brains exerts an influence on the amount of PrPC and its cleavage properties and may affect the PrP conversion by depleted availability of functional PrP full length.