Prion diseases are devastating illnesses of the central nervous system and the outcome is invariably lethal. Fusion proteins consisting of cellular prion protein (PrPc) and the Fc domain of immunoglobulin 1, designated PrP-Fc, will be employed for the molecular characterization and immunochemical studies of PrPsc, the disease causing PrP isoform. We propose to produce and characterize several variants of PrP-Fc including mutant PrP molecules. We plan to investigate the interaction between PrP c and PrP sc using PrPFc, which was recently reported by others to inhibit PrPsc formation in transgenic mice. Preliminary studies indicate that PrP-Fc binds to PrPsc in crude extracts prepared from brain. We plan to exploit this property sc and develop new approaches for the detection of PrPsc in tissues of prion-infected animals and humans. Whether PrP-Fc can be used for the measurement of PrPsc in infected tissues remains to be established. Mutants of PrP in the PrP-Fc fusion protein may prove particularly useful in these studies if the affinity for PrPsc can be substantially increased. Not only might such mutant PrP-Fc proteins prove to be useful for measuring PrPsc but such molecules might also form the basis for a novel therapeutic approach to prion diseases. If the foregoing studies yield the anticipated results, a similar approach might be applicable to developing an antemortem diagnostic test to Alzheimer's disease (AD).
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