Protease-sensitive scrapie prion protein in aggregates of heterogeneous sizes

The pathological prion protein PrPSc is the only known component of the infectious prion. In cells infected with prions, PrPSc is formed posttranslationally by the refolding of the benign cell surface glycoprotein PrPC into an aberrant conformation. The two PrP isoforms possess very different properties, as PrPSc has a protease-resistant core, forms very large amyloidic aggregates in detergents, and is only weakly immunoreactive in its native form. We now show that prion-infected rodent brains and cultured cells contain previously unrecognized protease-sensitive PrPSc varieties. In both ionic (Sarkosyl) and nonionic (n-octyl beta-D-glucopyranoside) detergents, the novel protease-sensitive PrPSc species formed aggregates as small as 600 kDa, as measured by gel filtration. The denaturation dependence of PrPSc immunoreactivty correlated with the size of the aggregate. The small PrPSc aggregates described here are consistent with the previous demonstration of scrapie infectivity in brain fractions with a sedimentation coefficient as small as 40 S [Prusiner et al. (1980) J. Neurochem. 35, 574-582]. Our results demonstrate for the first time that prion-infected tissues contain protease-sensitive PrPSc molecules that form low MW aggregates. Whether these new PrPSc species play a role in the biogenesis or the pathogenesis of prions remains to be established.