Prion diseases are fatal neurodegenerative disorders that are also infectious. Prions are composed of a misfolded, aggregated form of a normal cellular protein that is highly expressed in neurons. Prion-infected individuals show variability in the clinical signs and brain regions that selectively accumulate prions, even within the same species expressing the same prion protein sequence. The basis of these divergent disease phenotypes is unclear, but is thought to be due to different conformations of the misfolded prion protein, known as strains.
Researchers have characterized the neuropathology and biochemical properties of prion strains that efficiently or poorly invade the CNS from their peripheral entry site. Prion strains that efficiently invade the CNS also cause a rapidly terminal disease after an intracerebral exposure. These rapidly lethal strains were unstable when exposed to denaturants or high temperatures, and efficiently accumulated misfolded prion protein over a short incubation period in vivo. These findings indicate that the most invasive, rapidly spreading strains are also the least conformationally stable.
Biochemical Properties of Highly Neuroinvasive Prion Strains. (2012) PLoS Pathog 8(2): e1002522. doi:10.1371/journal.ppat.1002522
Infectious prions propagate from peripheral entry sites into the central nervous system (CNS), where they cause progressive neurodegeneration that ultimately leads to death. Yet the pathogenesis of prion disease can vary dramatically depending on the strain, or conformational variant of the aberrantly folded and aggregated protein, PrPSc. Although most prion strains invade the CNS, some prion strains cannot gain entry and do not cause clinical signs of disease. The conformational basis for this remarkable variation in the pathogenesis among strains is unclear. Using mouse-adapted prion strains, here we show that highly neuroinvasive prion strains primarily form diffuse aggregates in brain and are noncongophilic, conformationally unstable in denaturing conditions, and lead to rapidly lethal disease. These neuroinvasive strains efficiently generate PrPSc over short incubation periods. In contrast, the weakly neuroinvasive prion strains form large fibrillary plaques and are stable, congophilic, and inefficiently generate PrPSc over long incubation periods. Overall, these results indicate that the most neuroinvasive prion strains are also the least stable, and support the concept that the efficient replication and unstable nature of the most rapidly converting prions may be a feature linked to their efficient spread into the CNS.