Proteinase‐resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity

Abstract

Multiple lines of evidence indicate that PrPSc, found only in scrapie, is a necessary component of the infectious scrapie agent. Equally compelling is the evidence that its accumulation in the brain causes the neuropathology characteristic of scrapie. We measured the regional concentration of PrPSc in nine brain regions throughout the course of scrapie in the Syrian hamster following intrathalamic inoculation of prions. PrPSc was compared to the regional concentration of glial fibrillary acidic protein, a measure of reactive astrocytic gliosis. PrPSc was detected first in the thalamus 14 to 21 days postinoculation and next in the septum at 28 days. Initiation of PrPSc synthesis and accumulation in the thalamus was attributable to the inoculum and in the septum to ventricular spread of de novo synthesized PrPSc. The timing and pattern of PrPSc accumulation in all other brain regions suggested transmission along neuroanatomic pathways. Reactive astrocytic gliosis followed PrPSc accumulation in each region by 1 to 2 weeks. Brain PrPSc, determined by summing the concentrations in each brain region, correlated well with scrapie infectivity titers throughout the course of infection (correlation coefficient = 0.975; slope of linear regression line = 1.136). Our results support the hypothesis that PrPSc participates in both the etiology and pathogenesis of prion diseases.

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

“…In the white matter, bundles of myelinated axons contained PrP Sc but were devoid of PrP C . These findings suggest that prions are transported along axons and are in agreement with earlier findings in which scrapie infectivity was found to migrate in a pattern consistent with retrograde transport (210)(211)(212).…”

“…1) have been used to characterize prion strains (276), but recent studies argue that such profiles are not an intrinsic feature of strains (277,278). The mechanism by which prion strains modify the pattern of spongiform degeneration was perplexing, since earlier investigations had shown that PrP Sc deposition precedes neuronal vacuolation and reactive gliosis (212,231). When FFI prions were inoculated into Tg(MHu2M) mice, PrP Sc was confined largely to the thalamus (Fig.…”

Decontamination of surgical instruments from prion proteins: in vitro studies on the detachment, destabilization and degradation of PrPSc bound to steel surfaces

“…According to the prion hypothesis (Prusiner, 1982(Prusiner, , 1998, TSE agents (socalled proteinaceous infectious particles or prions) consist essentially -if not entirely -of a misfolded form of the prion protein (PrP), which is known as PrP Sc and derived from a host-encoded cellular precursor (PrP C ). Although the exact molecular nature of TSE agents remains to be determined, there is substantial evidence that PrP Sc (or its protease-resistant core, PrP27-30) provides a practical biochemical marker for these pathogens (McKinley et al, 1983;Jendroska et al, 1991;Beekes et al, 1996;Baldauf et al, 1997;Ironside, 2000;Wadsworth et al, 2001).…”

The Neurochemistry of Prion Diseases

“…The pattern and rate of PrPSc accumulation in Syrian hamsters inoculated in the thalamus with SHa(Sc237) prions have been examined in detail both by neurochemical measurements of P r p levels in dissected brain regions (DeArmond et al, 1987;Jendroska et al, 1991) and by the histoblot method . De novo synthesis of PrP% begins at the site of inoculation of SHa(Sc237) prions in the thalamus, where its accumulation becomes detectable 14-2 1 days postinoculation by the neurochemical method (Fig.…”