Protease-sensitive scrapie prion protein in aggregates of heterogeneous sizes

The pathological prion protein PrP^Sc is the only known component of the infectious prion. In cells infected with prions, PrP^Sc is formed posttranslationally by the refolding of the benign cell surface glycoprotein PrP^C into an aberrant conformation. The two PrP isoforms possess very different properties, as PrP^Sc 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 PrP^Sc varieties. In both ionic (Sarkosyl) and nonionic (n-octyl β-D-glucopyranoside) detergents, the novel protease-sensitive PrP^Sc species formed aggregates as small as 600 kDa, as measured by gel filtration. The denaturation dependence of PrP^Sc immunoreactivty correlated with the size of the aggregate. The small PrP^Sc 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 PrP^Sc molecules that form low MW aggregates. Whether these new PrP^Sc species play a role in the biogenesis or the pathogenesis of prions remains to be established.