title: Prion Infectivity Plateaus and Conversion to Symptomatic Disease Originate from Falling Precursor Levels and Increased Levels of Oligomeric PrPSc Species.
abstract: In lethal prion neurodegenerative diseases, misfolded prion proteins (PrP(Sc)) replicate by redirecting the folding of the cellular prion glycoprotein (PrP(C)). Infections of different durations can have a subclinical phase with constant levels of infectious particles, but the mechanisms underlying this plateau and a subsequent exit to overt clinical disease are unknown. Using tandem biophysical techniques, we show that attenuated accumulation of infectious particles in presymptomatic disease is preceded by a progressive fall in PrP(C) level, which constricts replication rate and thereby causes the plateau effect. Furthermore, disease symptoms occurred at the threshold associated with increasing levels of small, relatively less protease-resistant oligomeric prion particles (oPrP(Sc)). Although a hypothetical lethal isoform of PrP cannot be excluded, our data argue that diminishing residual PrP(C) levels and continuously increasing levels of oPrP(Sc) are crucial determinants in the transition from presymptomatic to symptomatic prion disease.
  
  
  OBJECTIVE
  Prions are infectious agents that cause lethal brain diseases; they arise from misfolding of a cell surface protein, PrP(C) to a form called PrP(Sc). Prion infections can have long latencies even though there is no protective immune response. Accumulation of infectious prion particles has been suggested to always reach the same plateau in the brain during latent periods, with clinical disease only occurring when hypothetical toxic forms (called PrP(L) or TPrP) begin to accumulate. We show here that infectivity plateaus arise because PrP(C) precursor levels become downregulated and that the duration of latent periods can be accounted for by the level of residual PrP(C), which transduces a toxic effect, along with the amount of oligomeric forms of PrP(Sc).
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Mays
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: van der Merwe
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Chae
authors.initials: C
authors.lastname: Kim
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio, USA Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Haldiman
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada Department of Biological Sciences, Division of Neurology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Debbie
authors.initials: D
authors.lastname: McKenzie
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio, USA Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA Department of Neurology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jiri G
authors.initials: JG
authors.lastname: Safar
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada Department of Biological Sciences, Division of Neurology, University of Alberta, Edmonton, Alberta, Canada Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada david.westaway@ualberta.ca.
authors.forename: David
authors.initials: D
authors.lastname: Westaway
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D055503:Protein Multimerization
chemical_list: D018620:PrPSc Proteins