title: Single particle analysis of manganese-induced prion protein aggregates.
abstract: Prion diseases are characterized by the conversion of the cellular prion protein (PrP(C)) to a disease-specific aggregated isoform (PrP(Sc)). We have shown that Mn(2+) ions amplify aggregation, whereas Cu(2+) has an inhibitory effect. To characterize Mn(2+)-induced aggregates, we used cross-correlation analysis as well as scanning for intensely fluorescent targets in an SDS-dependent aggregation assay with fluorescently labeled PrP. We found that the effect of Mn(2+) was mainly due to the association of preformed PrP oligomers to larger aggregates, rapidly reversible by EDTA, and independent of the histidine-dependent copper-binding sites of PrP, suggesting that Mn(2+) induces reversible intermolecular binding. In contrast, the inhibitory effect of Cu(2+) required binding to histidine-containing binding sites, indicating that binding of copper affects the structure of PrP(C) which in turn modifies the susceptibility to manganese and the ability to aggregate. These findings suggest that copper and manganese may also affect prion propagation in vivo.
authors.affiliation: Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Levin
authors.forename: Uwe
authors.initials: U
authors.lastname: Bertsch
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
mesh_terms: D001665:Binding Sites; D003300:Copper / Q000378:metabolism; D004492:Edetic Acid / Q000494:pharmacology; D006801:Humans; D008345:Manganese / Q000494:pharmacology*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011489:Protein Denaturation / Q000187:drug effects
chemical_list: D011328:Prions; D008345:Manganese; D003300:Copper; D004492:Edetic Acid