Prions are infectious proteins composed of β-sheet conformers. These β-sheet or PrP Sc conformers are derived from misfolding of the prion protein PrP. These β-sheet rich conformers are responsible for number of diseases like scrapie in Sheep, bovine spongiform encephalopathy (BSE) also known as mad cow disease in cattle and Creutzfeldt–Jakob disease (CJD) and kuru in humans. Prions are characterized by the incubation time and neuropathology they elicit in a particular host and hence occur in distinct strains. The protein-only hypothesis assumes that each strain is associated with different conformer of PrP Sc. Cell-free conversion experiments and protein misfolding cyclic amplification (PMCA) have shown that conformational templating is possible at protein level.
Prion strain identity is thought to be encoded by PrP Sc conformations. Here the authors determine the cell culture properties of prions using cell panel assays. They show that when prions were transferred from brain to cultured cells, prions strain changed and was more cell adapted. However, when prions were returned from cells to brain, they became brain adapted again. The cell adapted strain outcompeted their brain counterparts in cell culture and brain adapted strain outcompeted when they were returned to brain. Experiments conducted with inhibitor swainsonine showed that when prions were grown in presence of inhibitor the resistant strain outgrew the sensitive strain and viseversa when grown in absence of the inhibitor. The authors suggest a quasispecies concept and Darwainian evolution for prions. They show that pions are subjected to mutations and to selective amplification depending on the different environments. The authors also suggest that drug resisstance would be less in drugs targeting PrP than drugs inhibiting PrP Sc.
This article was contributed by Dr. Shailaja Divekar, Georgetown University Medical Center, Washington DC
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