Prion Infectivity Plateaus and Conversion to Symptomatic Disease Originate from Falling Precursor Levels and Increased Levels of Oligomeric PrP ^Sc 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. IMPORTANCEPrions 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 . Prions are proteinaceous, infectious particles responsible for a group of incurable neurodegenerative diseases in humans and animals. A posttranslationally misfolded version of the cellular prion protein (PrP C ), known as PrP Sc , is the primary component of a prion and propagates by acting as a template for the conformational conversion of PrP C substrate (1). Analysis of brain material by prion bioassays has shown that infectivity plateaus can exist early during disease, suggesting that infections can be divided into an infectivity phase and a toxicity phase (2-4). The accumulation of a hypothetical toxic PrP form (PrP L , "L" for lethal), distinct from PrP Sc , has been proposed to explain the transition from a subclinical phase to the appearance of clinical signs and progression to end-stage disease at the time when the prion levels plateau. It has been further suggested that prions are infectious, but nontoxic, entities that act as a catalyst for the generation of toxic PrP L at a rate with direct proportionality to PrP C expression levels in the animal models used for these experiments (2). However, this hypothetical protein has yet to be isolated.In other studies, based on falling levels of the PrP-like Sh...

Goats naturally devoid of PrPC are resistant to scrapie

“…Heterozygous goats had, on average, 29% longer incubation time (773 versus 601 days) and a much slower progression in the development of clinical signs than PRNP +/+ goats. Interestingly, inoculation of heterozygous (Prnp 0/+ ) mice with RML mouse-adapted scrapie resulted in a 70 to 120% increase in incubation time when compared with wild type mice [36][37][38]. This suggests that the protective effect of PRNP Ter heterozygosity in goats, which is a natural host for scrapie, seems lower than expected based on the results from laboratory rodents.…”

Role of polysaccharide and lipid in lipopolysaccharide induced prion protein conversion

“…Oligomerization has shown to be critical for conversion potency in the propagation of native PrP c to PrP Sc in PMCA and QuIC assays 39 . Furthermore, oligomers are linked to a form of relatively less protease resistant prions that peak at the transition from asymptomatic to symptomatic prion disease 40 . Despite oligomers usually displaying less protease resistance than fibrils, 41,42 the PrP β formed by LPS and dLPS contain a 17/18 kDa PK resistant fragment at a weight ratio of 1:400 PK to PrP.…”

Prion Strain Diversity

“…These data suggest that the blocking strain is sequestering PrP C or preventing its use by the superinfecting strain (Shikiya et al 2010). Recent evidence indicates that just before the onset of clinical disease, PrP C expression is downregulated in the CNS (Mays et al 2014(Mays et al , 2015. This could provide another mechanism by which the blocking strain limits the number of replication sites; however, it remains to be established whether PrP C downregulation occurs in neurons at the early time points postinfection when the blocking strain is able to interfere with the superinfecting strain.…”