Prions

Weissmann et al. “Prions on the move.” (2011) EMBO Reports 12(11) pgs 1109 – 1117.

             

                Prions are the infectious agents responsible for Creutzfeldt-Jakob disease, scrapie and bovine spongiform encephalopathy.  PrP^C is a 208 amino acid protein with two potential glycosylation sites.  Typically, it is found GPI-anchored to the plasma membrane outer surface.  PrP^SC is an aggregate of misfolded PrP molecules.  The aggregate recruits properly folded PrP to promote sequestration, protein misfolding and aggregate growth.

                A recent review by Browning and colleagues explores the recent literature to explain the leading theories on “barrier to transmission” and how prions can adapt to new environments.

                Consider a situation where the donor PrP is different in amino acid sequence from the recipient PrP.  Recipient PrP may have trouble joining the donor PrP aggregate for two reasons.  One, the differences in amino acid sequence may not allow the recipient PrP to adopt the necessary conformation needed for stable addition.  However, even when the PrP sequence is exactly the same, recipient PrP may still have problems, leading to the idea that different cellular environments and perhaps other proteins are involved in aggregate growth.

                An interesting study took 22L prions that could chronically infect PK1 cells in the presence of R33 cells and swainsonine.  Swainsonine is a small molecule that causes misglycosylation of proteins.  After forty population doublings, the prion population had become R33-incompetent and was sensitive to swainsonine.  When these new prions were placed back in the environment of the brain, the population changed back to being R33-competent and swainsonine insensitive.  

                The authors offer an excellent summation of these findings: “…a prion strain is a quasi-species, consisting of a major component and many variants, which are constantly being generated and selected against in a particular environment, as described earlier for RNA viruses and retroviruses.”  Comparing the adaptability of prions, a misfolded protein, to that of viruses, which bear genetic material and can respond to cellular changes with more plasticity, is fascinating.  The field strongly feels the changes in properties are most likely due to change in PrP^SC conformation.  

                Unfortunately, it also means that prions can develop drug resistance.  For this reason, many feel the best way to stop aggregate formation is to stop PrP synthesis or accelerate its turnover.  This idea has merit since PrP depletion in mice does not lead to devastating side effects.  However, the authors do end on the downer by saying that “no effective therapy is on the horizon.”