PrPST, a Soluble, Protease Resistant and Truncated PrP Form Features in the Pathogenesis of a Genetic Prion Disease

Abstract

While the conversion of PrPC into PrPSc in the transmissible form of prion disease requires a preexisting PrPSc seed, in genetic prion disease accumulation of disease related PrP could be associated with biochemical and metabolic modifications resulting from the designated PrP mutation. To investigate this possibility, we looked into the time related changes of PrP proteins in the brains of TgMHu2ME199K/wt mice, a line modeling for heterozygous genetic prion disease linked to the E200K PrP mutation. We found that while oligomeric entities of mutant E199KPrP exist at all ages, aggregates of wt PrP in the same brains presented only in advanced disease, indicating a late onset conversion process. We also show that most PK resistant PrP in TgMHu2ME199K mice is soluble and truncated (PrPST), a pathogenic form never before associated with prion disease. We next looked into brain samples from E200K patients and found that both PK resistant PrPs, PrPST as in TgMHu2ME199K mice, and “classical” PrPSc as in infectious prion diseases, coincide in the patient's post mortem brains. We hypothesize that aberrant metabolism of mutant PrPs may result in the formation of previously unknown forms of the prion protein and that these may be central for the fatal outcome of the genetic prion condition.

Transgenic Fatal Familial Insomnia Mice Indicate Prion Infectivity-Independent Mechanisms of Pathogenesis and Phenotypic Expression of Disease

“…In contrast to the mitigating effect on sleep abnormalities, co-expression of WT PrP does not significantly modify the time of onset and progression of motor dysfunction or prolong survival of Tg(FFI) mice, consistent with the dominant mode of inheritance of FFI and with similar observations in other mutant PrP mice [ 14 , 19 , 43 ]. Thus, WT PrP influences only some aspects of the Tg(FFI) phenotype, perhaps those that are more dependent on a physiological function of PrP in neuronal excitability [ 44 ].…”

Chronic Progressive Neurodegeneration in a Transgenic Mouse Model of Prion Disease

“…Insertion of the E to K mutation at the relevant position (codon 199, representing the human E200K mutation) led to the generation of a transgenic mouse line (TgMHu2ME199K/KO). These mice suffer from progressive neurological symptoms as early as 5–6 month of age and deteriorate to a terminal condition several months thereafter, concomitant with the accumulation of a truncated form of protein kinase-resistant PrP (Kovacs et al, 2010; Friedman-Levi et al, 2011, 2013). TgMHu2ME199K/KO mice exhibit typical pathological features of human CJD, such as gliosis and lipid oxidation, and have already been used successfully to test the activity of a candidate reagent (Mizrahi et al, 2014)…”

Molecular dynamics studies on the NMR and X-ray structures of rabbit prion proteins

“…Sweeting et al (2013) produced X-ray structures of mutants in the β2-α2 loop and reported that the helix-capping motif in the β2-α2 loop modulates β-state misfolding in RaPrP, and still acknowledged "rabbit PrP, a resistant species" (Sweeting et al (2013)). Friedman- Levi et al (2013) reported "pAb RTC and EP1802Y (EP), a rabbit α PrP mAb directed against the CITQYER ESQAYYQRGS sequence present at the C-terminal part of human PrP, just before the PrP GPI anchor" (Friedman-Levi et al (2013)). Timmes et al (2013) used R20 as the rabbit polyclonal anti-PrP antibody (Timmes et al (2013)).…”