Biochemical properties of highly neuroinvasive prion strains

Abstract

Prion diseases are fatal neurodegenerative diseases caused by the conformational conversion of the cellular prion protein, PrPC, into an aggregated, β‐sheet rich isoform, PrPSc. Prion pathogenesis can vary dramatically depending on the strain, thought to be conformational variants of PrPSc, yet the structural basis for the differences in pathogenesis in unclear. Using an array of mouseadapted prion strains, here we define the neuropathology and biochemical features of prion strains that efficiently or poorly invade the CNS from their peripheral entry site. In brain sections, we find that the highly neuroinvasive prion strains primarily form diffuse aggregates that do not bind to the amyloid binding dye, Congo red. Biochemically these aggregates are conformationally unstable in denaturing conditions. These neuroinvasive strains also efficiently generate PrPSc over short incubation periods. In contrast, the poorly neuroinvasive strains formed dense, Congo red binding aggregates that were conformationally stable. Our findings indicate that the most neuroinvasive, efficiently spreading strains are also the least conformationally stable, and support the concept that the unstable nature of the most rapidly converting prions may be a feature linked to their efficient spread into the CNS.