title: Assessment of strain-specific PrP(Sc) elongation rates revealed a transformation of PrP(Sc) properties during protein misfolding cyclic amplification.
abstract: Prion replication is believed to consist of two components, a growth or elongation of infectious isoform of the prion protein (PrP(Sc)) particles and their fragmentation, a process that provides new replication centers. The current study introduced an experimental approach that employs Protein Misfolding Cyclic Amplification with beads (PMCAb) and relies on a series of kinetic experiments for assessing elongation rates of PrP(Sc) particles. Four prion strains including two strains with short incubation times to disease (263K and Hyper) and two strains with very long incubation times (SSLOW and LOTSS) were tested. The elongation rate of brain-derived PrP(Sc) was found to be strain-specific. Strains with short incubation times had higher rates than strains with long incubation times. Surprisingly, the strain-specific elongation rates increased substantially for all four strains after they were subjected to six rounds of serial PMCAb. In parallel to an increase in elongation rates, the percentages of diglycosylated PrP glycoforms increased in PMCAb-derived PrP(Sc) comparing to those of brain-derived PrP(Sc). These results suggest that PMCAb selects the same molecular features regardless of strain initial characteristics and that convergent evolution of PrP(Sc) properties occurred during in vitro amplification. These results are consistent with the hypothesis that each prion strain is comprised of a variety of conformers or 'quasi-species' and that change in the prion replication environment gives selective advantage to those conformers that replicate most effectively under specific environment.
authors: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors: Nuria
authors: N
authors: Gonzalez-Montalban
authors: Ilia V
authors: IV
authors: Baskakov
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D006224:Cricetinae; D006031:Glycosylation; D007700:Kinetics; D015233:Models, Statistical; D008962:Models, Theoretical; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism / Q000503:physiopathology*; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D020033:Protein Isoforms
chemical_list: D018620:PrPSc Proteins; D020033:Protein Isoforms