This refers to the observation that transmission of PrPSc between two different species is typically far less efficient than transmission within the same species. This barrier may be partially due to changes in amino acid sequence, but can also be due to changes in the self-propagating structure of the protein itself. Indeed, even within a single species, pathological D-Pantothenic acid sodium variation in TSEs and different biochemical signatures of PrPSc have been observed, leading to the isolation of distinct PrPSc types. These different types of PrPSc are called prion strains, and represent amyloid conformations of PrP that are structurally unique. In many cases, different prion strains show differences in biochemical properties, such as protease resistance or denaturant sensitivity, which correlate with variation in pathology and the time course of disease. However, in other cases, prion strains have been isolated that vary in pathology, yet remain biochemically indistinguishable, according to the levels of sensitivity available with current assays. Moreover, while genetic polymorphisms in PrP bias the formation of particular conformations of PrPSc, a single primary sequence can propagate a multitude of distinct prion strains. Indeed, it has been estimated that the range of heterogeneity seen in samples from patients with sporadic CJD represents over 30 distinct prion strains. Clearly, the structural limits of amyloid polymorphism of prion strains are quite large. Interestingly, functionally distinct prion Gambogic-acid proteins exist in fungi such as the yeast Saccharomyces cerevisiae. Yeast prion proteins share many of the same misfolding and aggregation characteristics as the proteins associated with human protein conformational disorders. As such, yeast has provided a tractable model system to investigate many facets of protein aggregation and prion biology, including that of prion strain diversity. As in mammals, prion strains in yeast are conformationally distinct, self-propagating amyloid structures. This formation of amyloid in yeast leads to changes in cellular phenotypes, which typically resemble a loss-of-function phenotype of the prion protein. One of the most well-studied prion proteins in S. cerevisiae is the translation termination factor Sup35. Sup35 is the eRF3 that normally exists in a complex that functions to recognize stop codons in mRNA and facilitate the release of polypeptide chains from ribosomes. Conversion of Sup35 into its prion form,, establishes a loss-of-function phenotype that is dominant and inherited in a non-Mendelian fashion. In cells, much 
of the Sup35 is sequestered into prion aggregates, thereby impairing translation termination and causing readthrough of stop codons. variants have been broadly classified into categories based on the degree of nonsense suppression. Two wellcharacterized variants are strong and weak. Cells propagating the strong variant exhibit a greater amount of nonsense suppression as compared to cells propagating the weak variant. Studies of strong and weak led to a model that proposed an explanation for how differences in the biochemical properties of these variants correlate with differences in biological phenotypes. This model posits that decreased fiber stability results in increased fragmentation, thereby giving rise to a greater number of prion seeds, and thus more fibril “free ends” that can recruit and sequester natively-folded Sup35. Ultimately, the more ��free ends�� available are hypothesized to correlate to an increased rate of fiber growth that, in the case of the prion, modulates the strength of the nonsense suppression phenotype as the efficiency of translation termination is linked to the size of the soluble, active pool of Sup35.