The Issue of Prions Strains

There are many different strains of scrapie which are differentiated by their incubation period, lesion pattern, physical symptoms. These strains can be transmitted in inbred mouse strains that are homozygous for a single PrP genotype; serial transmission results in no change in the "strain" characteristics. This implies that a specific PrP is converted to a specific PrP^sc strain which is distinct from other strains (Bessen et al.,1995).

The existence of scrapie strains has been difficult to explain based on the protein-only hypothesis. A number of investigators have suggested that prion protein is not the infective agent or that it does not act alone.

In order to investigate the mechanism of scrapie strain propagation (Bessen et al.,1995). tested whether the biochemical differences between PrP^sc from hyper (HY) and drowsy (DY) hamster prion disease could be transmitted. Both the HY and DY PrP^sc are post-translationally derived from the PrP precursor, they are cleaved at different amino-terminal sites by proteinase K. Using a cell-free conversion system, addition of HY PrP^sc or DY PrP^sc produced "strain specific" PrP^sc from the same unglycosylated PrP precursor. The two distinct sets of protease-resistant PrP^sc products provide evidence that self-propagation of PrP^sc polymers having distinct three-dimensional structures could be the molecular basis of scrapie strains. The PrP^sc strains may be alternative conformations or packing arrangements of PrP^sc polymers.

BSE in cattle seems to be caused by a single prion strain type with unusually persistent phenotypic properties (following passage in other species). The BSE "signature" may be detectable following passage in humans (Bruce et al. 1994).

There are some examples of protein conformation change inducing infectivity without any genetic alteration. Yeast Ure2p protein can be converted to an inactive conformation by other Ure protein. There is no genetic mutation in the yeast with the altered phenotype.