Normal cellular prion protein with a methionine at position 129 has a more exposed helix 1 and is more prone to aggregate

The human prion gene, PRNP, has two allelic forms that encode either a methionine or valine at codon 129. This polymorphism strongly influences the pathogenesis of prion disease. However, the underlying mechanism remains unclear. We compared the conformation between wild-type human prion protein (rPrP^C) with either a valine or methionine at position 129, using a panel of monoclonal antibodies that are specific for epitopes along the entire protein. We found that rPrP^C(129M) has a more exposed helix 1 region compared to rPrP^C(129V). Helix 1 is important in the aggregation process. Accordingly, rPrP^C(129M) aggregates at a faster rate and forms more aggregate than rPrP^C(129V). In addition, by using a rPrP with a pathogenic mutation of five additional octapeptide repeat insertions, rPrP^(129M)/10OR, as "seeds", we showed that rPrP^(129M)/10OR promotes the aggregation of rPrP^C(129M) more efficiently than rPrP^C(129V). These findings provide a possible mechanism underlying the influence of residue 129 on human prion disease.