Differential effects of prion particle size on infectivity in vivo and in vitro.
The conversion of cellular prion protein to the disease-associated isoform (PrP(Sc)) has been suggested to follow a mechanism of seeded aggregation. Here, we show that fragmentation of PrP(Sc) aggregates by sonication increases converting activity in cell culture in a way similar to in vitro conversion assays. In contrast, under the same conditions the infectious titer of sonicated samples in vivo was reduced. We modified the size distribution of PrP(Sc) by adsorption to nitrocellulose, which resulted in a reduction of the infectious titer in non-sonicated samples and an increase in sonicated samples. Our results indicate that NC-adsorption can (i) block some active sites of PrP(Sc) aggregates and (ii) reduce the rate of clearance from the brain. For large particles with low clearance the effect of NC-particles on the number of available active sites may dominate, whereas for smaller particles (i.e. sonicated samples) the effect of NC-adsorption on clearance dominates resulting in increased infectivity.
Weber
Petra
P
Center for Neuropathology and Prion Research, Ludwig Maximilians University of Munich, Feodor-Lynen-Strasse 23, 81377 Munich, Germany.
Reznicek
Lukas
L
Mitteregger
Gerda
G
Kretzschmar
Hans
H
Giese
Armin
A
D000818:Animals; D001681:Biological Assay; D001923:Brain Chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D010316:Particle Size; D018620:PrPSc Proteins / Q000378:metabolism* / Q000633:toxicity*; D017096:Prion Diseases / Q000209:etiology*; D017510:Protein Folding; D013010:Sonication
D018620:PrPSc Proteins