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

• DOI: 10.1007/s00018-007-7478-z
• Publication Date: 2008-01-12T14:50:32Z
• Authors: J. Yuan; Z. Dong; J.-P. Guo; J. McGeehan; X. Xiao; J. Wang; I. Cali; P. L. McGeer; N. R. Cashman; R. Bessen; W. K. Surewicz; G. Kneale; R. B. Petersen; P. Gambetti; W. Q. Zou
• Keywords: Strain (injury); Residue (chemistry)

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.