Substitution of histidine 95 by tyrosine in the prion protein causes spontaneous neurodegeneration in transgenic mice

Prion diseases are neurodegenerative disorders caused by a change in conformation of the prion protein from the cellular form (PrPC) to a misfolded isoform (PrPSc). PrPC is a copper binding protein via histidine residues in the octapeptide repeats (OR) and the non-OR region located at the N-terminus. Although the functional implication of copper binding to PrPC is still under investigation, copper may play a role in prion disease. In this study, we describe transgenic mice expressing mouse prion protein replacing histidine 95 by tyrosine (PrP H95Y) to disrupt the non-OR copper-binding site. Transgenic mice overexpressing PrP H95Y showed clinical signs and died at about 100 days with spongiform degeneration and PK-resistant PrP. Inoculation of brain homogenate from mice overexpressing PrP H95Y to Tga20 mice expressing wild-type PrP also causes lethal, spongiform encephalopathy. We conclude that this substitution could promote PrPC-PrPSc conversion and induce spontaneous prion disease in vivo.