In this regard, the increasingly recognized co-occurrence of different PrPSc types in the same brain [74,85,90,93,102–108] and the recognition that protease-sensitive pathological isoforms of PrP (distinct from prototypical PrPSc) may have a significant role in both animal and human prion disease [94,99,109–116] has further confounded progress. This evidence concerns the gene PRNP and prion disease.