Walsh & Hoyt: Propagation and Pathophysiology of Prion Diseases

Several theories have been proposed to explain the mechanism by which inoculation with PrPSc induces modification of the analogous protein in the host. All of these theories are anchored by the concept that PrPSc induces a conformational change in PrPC, converting it to PrPSc. This novel form of cyclic autocatalytic amplification is apparently unique to prion diseases. The mechanism of cell injury in prion diseases remains elusive, and both PrPSc and PrPC are required for disease to occur; transgenic mice with both PrP alleles ablated (PrP knockout or PrP0/0 mice) are resistant to inoculation with prions, consistent with the hypothesis that an interaction between PrPSc and host PrPC is required for subsequent propagation of PrPSc and neurotoxicity. Although prion diseases have been considered universally lethal, the existence of subclinical prion disease in animal models has raised the possibility of subclinical human disease with a corresponding occult PrPSc reservoir in the population.