Accessibility of a critical prion protein region involved in strain recognition and its implications for the early detection of prions

Human prion diseases are characterized by the accumulation in the brain of proteinase K (PK)-resistant prion protein designated PrP27-30 detectable by the 3F4 antibody against human PrP109-112. We recently identified a new PK-resistant PrP species, designated PrP(*20), in uninfected human and animal brains. It was preferentially detected with the 1E4 antibody against human PrP 97-108 but not with the anti-PrP 3F4 antibody, although the 3F4 epitope is adjacent to the 1E4 epitope in the PrP(*20) molecule. The present study reveals that removal of the N-terminal amino acids up to residue 91 significantly increases accessibility of the 1E4 antibody to PrP of brains and cultured cells. In contrast to cells expressing wild-type PrP, cells expressing pathogenic mutant PrP accumulate not only PrP(*20) but also a small amount of 3F4-detected PK-resistant PrP27-30. Remarkably, during the course of human prion disease, a transition from an increase in 1E4-detected PrP(*20) to the occurrence of the 3F4-detected PrP27-30 was observed. Our study suggests that an increase in the level of PrP(*20) characterizes the early stages of prion diseases.