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Published on: March 12, 2018
Single particle analysis of manganese-induced prion protein aggregates
Johannes Levin1, Uwe Bertsch, Hans Kretzschmar
1Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität München, Germany.
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.
Insights
Manganese (Mn2+) ions promote prion protein (PrP) aggregation by linking existing oligomers, while copper (Cu2+) inhibits aggregation by altering PrP structure. These metal ions may influence prion diseases in living organisms.
Area of Science:
- Biochemistry
- Neuroscience
- Prion Biology
Background:
- Prion diseases involve the misfolding and aggregation of the cellular prion protein (PrP(C)) into disease-specific forms (PrP(Sc)).
- Metal ions like manganese (Mn2+) and copper (Cu2+) are known to interact with PrP.
Purpose of the Study:
- To investigate the distinct effects of Mn2+ and Cu2+ on prion protein aggregation.
- To characterize the mechanisms underlying Mn2+-induced aggregation and Cu2+ inhibition.
Main Methods:
- Utilized cross-correlation analysis and scanning for intensely fluorescent targets (SIFT).
- Employed an SDS-dependent aggregation assay with fluorescently labeled prion protein (PrP).
- Investigated the role of histidine-dependent copper-binding sites.
Main Results:
- Mn2+ amplifies PrP aggregation primarily by promoting the reversible association of preformed PrP oligomers into larger structures.
- Cu2+ inhibits PrP aggregation through a mechanism dependent on binding to histidine residues, altering PrP structure.
- The effects of Mn2+ were independent of the histidine-dependent copper-binding sites.
Conclusions:
- Mn2+ induces reversible intermolecular binding in PrP aggregates.
- Cu2+ binding to PrP modifies its structure, impacting its susceptibility to Mn2+ and aggregation propensity.
- These findings suggest a potential role for copper and manganese in prion propagation in vivo.
