Prion formation, but not clearance, is supported by protein misfolding cyclic amplification

Prion diseases are fatal transmissible neurodegenerative disorders that affect animals including humans. The kinetics of prion infectivity and PrPSc accumulation can differ between prion strains and within a single strain in different tissues. The net accumulation of PrPSc in animals is controlled by the relationship between the rate of PrPSc formation and clearance. Protein misfolding cyclic amplification (PMCA) is a powerful technique that faithfully recapitulates PrPSc formation and prion infectivity in a cell-free system. PMCA has been used as a surrogate for animal bioassay and can model species barriers, host range, strain co-factors and strain interference. In this study we investigated if degradation of PrPSc and/or prion infectivity occurs during PMCA. To accomplish this we performed PMCA under conditions that do not support PrPSc formation and did not observe either a reduction in PrPSc abundance or an extension of prion incubation period, compared to untreated control samples. These results indicate that prion clearance does not occur during PMCA. These data have significant implications for the interpretation of PMCA based experiments such as prion amplification rate, adaptation to new species and strain interference where production and clearance of prions can affect the outcome.