PrP Biology and Function

Abstract

The cellular prion protein (PrP c) is a determining factor in TSE pathogenesis, acting as substrate to the formation of abnormal, protease resistant PrP Sc. PrP c , which is widely expressed throughout the brain is encoded by the PRNP gene. It has long been accepted that polymorphisms occurring in the open reading frame specifically at positions 136, 154, 171 confer resistance/ susceptibility to scrapie infection in sheep and influence incubation times of the disease. 'Normal' cellular processing of PrP c includes a well-documented α-cleavage event, occurring at 115 (Val) of PrP (ovine) interrupting the so called neuro-toxic region. The truncated forms of PrP produced via this mechanism, known as N1 and C1 may play a role in neuro-protection. In sheep, C1 often displays as the prevailing form of PrP c representing between 10-80% of total PrP in the brain. We report a novel association between the ovine PrP polymorphism at codon 171 and levels of α cleavage in the brain, indicating that presence of C1 at higher levels may decrease susceptibility to disease. This hypothesized inhibitory effect was further investigated in fibrilization assays by mixing of recombinant full length PrP and C1 fragments representing resistant and susceptible PrP variants.