Aberrant metal binding by prion protein in human prion disease

Human prion diseases are characterized by the conversion of the normal prio n protein (PrPC) into a pathogenic isomer (PrPSc). Distinct PrPSc conformer s are associated with different subtypes of prion diseases. PrPC binds copp er and has antioxidation activity. Changes in metal-ion occupancy can lead to significant decline of the antioxidation activity and changes in conform ation of the protein. We studied the trace element status of brains from pa tients with sporadic Creutzfeldt-Jakob disease (sCJD). We found a decrease of up to 50% of copper and an increase in manganese of approximately 10-fol d in the brain tissues from sCJD subjects. We have also studied the metal o ccupancy of PrP in sCJD patients. We observed striking elevation of mangane se and, to a lesser extent, of zinc accompanied by significant reduction of copper bound to purified PrP in all sCJD variants, determined by the PrP g enotype and PrPSc type, combined. Both zinc and manganese were undetectable in PrPC preparations from controls. Copper and manganese changes were pron ounced in sCJD subjects homozygous for methionine at codon 129 and carrying PrPSc type-1. Anti-oxidation activity of purified PrP was dramatically red uced by up to 85% in the sCJD variants, and correlated with increased in ox idative stress markers in sCJD brains. These results suggest that altered m etal-ion occupancy of PrP plays a pivotal role in the pathogenesis of prion diseases. Since the metal changes differed in each sCJD variants, they may contribute to the diversity of PrPSc and disease phenotype in sCJD. Finall y, this study also presented two potential approaches in the diagnosis of C JD; the significant increase in brain manganese makes it potentially detect able by MRI, and the binding of manganese by PrP in sCJD might represent a novel diagnostic marker.