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

Yael Friedman-Levi,Kati Frid,Ruth Gabizon,Orli Binyamin,Michal Mizrahi,Giovanna R Mallucci

doi:10.1371/journal.pone.0069583

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.

Highlights

Detergent insoluble and PK resistant prion protein (PrP), known as PrPSc, was identified concomitantly with the enrichment of the prion agent in infected hamsters and mice [1]
Except for rare cases related to family intermarriages [21], most genetic Creutzfeldt-Jacob disease (CJD) patients are heterozygous for the mutation, thereby expressing both mutant and wt PrP [32]
Taking advantage of our TgMHu2ME199K/wt model of heterozygous E200K genetic CJD (gCJD), we looked into the time related changes in the biochemical properties of E199K and wt PrP from the asymptomatic early age to full blown disease

Summary

Introduction

Detergent insoluble and PK resistant PrP, known as PrPSc, was identified concomitantly with the enrichment of the prion agent in infected hamsters and mice [1]. Classical PrPSc could not be detected in brains of patients suffering from some forms of genetic prion diseases [5,7,8], which are autosomal dominant disorders linked to mutations in the gene encoding the prion protein (PrP) [9] [10]. The most common genetic CJD (gCJD) is the one linked to the E200K PrP mutation (substituting lysine for glutamate) [17,18]. This mutation was identified among Jews of Libyan origin as well as in subjects of other communities around the world [19]. While most E200K CJD patients are heterozygous for the mutation, disease presentation was faster to some degree in a small number of homozygous patients [21]

Methods

Results

Conclusion