Abstract
ABSTRACTPrion diseases are fatal and incurable neurodegenerative diseases of humans and animals. Despite years of research, no therapeutic agents have been developed that can effectively manage or reverse disease progression. Recently it has been identified that recombinant prion proteins (rPrP) expressed in bacteria can act as inhibitors of prion replication within the in vitro prion replication system protein misfolding cyclic amplification (PMCA). Here, within PMCA reactions amplifying a range of ruminant prions including distinct Prnp genotypes/host species and distinct prion strains, recombinant ovine VRQ PrP displayed consistent inhibition of prion replication and produced IC50 values of 122 and 171 nM for ovine scrapie and bovine BSE replication, respectively. These findings illustrate the therapeutic potential of rPrPs with distinct TSE diseases.
Highlights
Prion diseases, known as transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases that affect humans and animals
inhibitor concentration 50% (IC50) values were calculated for rVRQ, rARQ and rARR proteins when inhibiting the replication of a single ARQ/VRQ classical scrapie isolate (Fig. 2). rVRQ was the strongest inhibitor with a mean IC50, when calculated using the dot blot analysis method, of 122 nM, followed by rARQ (IC50 of 288 nM) and rARR (IC50 of 505 nM)
The analysis of protein misfolding cyclic amplification (PMCA) products inhibited by 1200 nM rVRQ or where no spike was present demonstrated that the dot blot method was detecting PrPSc and no residual PrPC signals were present (Fig. 2)
Summary
Known as transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases that affect humans and animals. Examples include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfelt Jakob disease (CJD) in humans. The central event in these diseases is the conversion of cellular prion protein (PrPC). Into the pathogenic isoform PrPSc.[1] the exact mechanism of conversion and the cause of pathogenesis remains unclear. It is proposed that PrPSc propagates by a template conversion model, whereby PrPC is converted into further copies of PrPSc independently of nucleic acids.[2] Through this mechanism PrPSc spreads throughout the central nervous system (CNS) of the host, eventually leading to the development of clinical
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