The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

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Abstract
Prion diseases are neurodegenerative disorders associatedwith a conformational change in the normal cellular isoform of the prionprotein, PrPC, to an abnormal scrapie isoform, PrPSC.Unlike the α‐helical PrPC, the protease‐resistant core ofPrPSC is predominantly β‐sheet and possesses a tendency topolymerize into amyloid fibrils. We performed experiments with two synthetichuman prion peptides, PrP(106‐126) and PrP(127‐147), to determine how peptidestructure affects neurotoxicity and protein‐membrane interactions. Peptidesolutions possessing β‐sheet and amyloid structures were neurotoxic toPC12 cells in vitro and bound with measurable affinities to cholesterol‐richphospholipid membranes at ambient conditions, but peptide solutions lackingstable β‐sheet structures and amyloid content were nontoxic and possessedless than one tenth of the binding affinities of the amyloid‐containingpeptides. Regardless of structure, the peptide binding affinities tocholesterol‐depleted membranes were greatly reduced. These results suggestthat the β‐sheet and amyloid structures of the prion peptides give riseto their toxicity and membrane binding affinities and that membrane bindingaffinity, especially in cholesterol‐rich environments, may be related totoxicity. Our results may have significance in understanding the role of thefibrillogenic cerebral deposits associated with some of the prion diseases inneurodegeneration and may have implications for other amyloidoses.