Protective Effect of Val-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease.

Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met) or valine (Val) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val Hu-PrP-positive humans with the emergence of new strain features.