Conformational conversion of prion protein in prion diseases

Abstract

Prion diseases are a group of infectious fatal neurodegenerative diseases. The conformational conversion of a cellular prion protein (PrP(C)) into an abnormal misfolded isoform (PrP(Sc)) is the key event in prion diseases pathology. Under normal conditions, the high-energy barrier separates PrP(C) from PrP(Sc) isoform. However, pathogenic mutations, modifications as well as some cofactors, such as glycosaminoglycans, nucleic acids, and lipids, could modulate the conformational conversion process. Understanding the mechanism of conformational conversion of prion protein is essential for the biomedical research and the treatment of prion diseases. Particularly, the characterization of cofactors interacting with prion protein might provide new diagnostic and therapeutic strategies.

Neutron Reflectometry Studies Define Prion Protein N-terminal Peptide Membrane Binding

“…Such observations raised questions over the potential role for cellular cofactors in PrP Sc propagation. Various anionic species have been suggested as cofactors in the production of infectious prions; these have included nucleic acids, glycosaminoglycans, and lipids (reviewed in (5,6)). In the first study to report use of the PMCA to produce genuinely infectious (transmissible in animal bioassay) rPrP species in the absence of an infectious disease-derived seed, a combination of 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (POPG) and nucleic acid cofactors were required (7).…”

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

“…Upon interaction, monomeric PrP Sc induces PrP C to convert into PrP Sc . However, until now, there is no experimental evidence for the existence of a stable PrP Sc monomer . PrP Sc seeds in this prion propagation process are not considered essential.…”

“…However, until now, there is no experimental evidence for the existence of a stable PrP Sc monomer. 168 PrP Sc seeds in this prion propagation process are not considered essential. Alternatively, in the more accredited seeded nucleation model by Jarrett and Lansbury, 169 This in vitro PrP res propagation recapitulates the species and strain specificity of prion transmission invivo.…”

Effects of peptidyl-prolyl isomerase 1 depletion in animal models of prion diseases

“…Guanidine-hydrochloride) [12]. The mechanism of conversion is not fully understood, but several factors, like glycosaminoglycans, lipids, nucleic acids, metals and phosphorylations are supposed to play an important role in this process [13][14][15][16][17][18][19][20]. An important technique named Protein Misfolding Cyclic Amplification (PMCA) has been developed in 2001 with the aim of mimicking the process of prion conversion in vitro in an accelerated manner [21].…”