The octapeptide repeats of prion protein play critical roles in the pathogenesis of prion diseases

Prion protein (PrP) is essential for the pathogenicity of prion diseases, a group of fatal neurodegenerative disorders affecting both humans and animals. The octapeptide repeats (OR) of PrP is a highly conserved structural feature; however, conflicting observations—that OR expansion causes inherited prion diseases while being dispensable for prion transmission—obscure its role in these disorders. We developed ΔOR mice by deleting the OR from the endogenous PrP-encoding gene, PRNP, which resulted in significantly prolonged survival times for mice inoculated with any of the five prion strains. Although disease characteristics were similar between terminally ill ΔOR and wild-type mice, the aggregation and conversion of PrP to the misfolded PrPSc were substantially delayed in ΔOR mice. This delay is attributable to reduced OR-OR self-association and diminished interactions between OR and the positively charged N-terminus of PrP. Additionally, the neurotoxic phase of the disease was both delayed and significantly prolonged in ΔOR mice. Our findings demonstrate the critical roles of OR in both PrP misfolding and neurotoxicity in prion diseases, highlighting OR as a promising therapeutic target that can mitigate both essential pathogenic processes in prion diseases.