The Prion Protein Preference of Sporadic Creutzfeldt-Jakob Disease Subtypes

Abstract

Background: Sporadic Creutzfeldt-Jakob disease (CJD) encompasses a spectrum of clinical phenotypes, the origin of which has not been fully elucidated. Results: Cell-free prion protein misfolding by sporadic CJD subtypes was affected by brain tissue composition and not related to absolute levels of PrP C . Conclusion: Tissue environment contributes to CJD subtype-specific prion protein misfolding. Significance: Non-PrP C cofactors may contribute to the development of sporadic CJD.

Molecular dynamics studies on 3D structures of the hydrophobic region PrP(109-136)

“…(2) the mutants A117V and M129V cause GSS [49,50,51] and CJD [52,53] respectively, (3) the β-sheet core of PrP Sc consists of three layers of β-strands E1(116-119), E2(129-132) and E3(160-164) [54], where E1 and E2 are in the hydrophobic region (109-136), (4) H111 is a residue of copper binding sites [55,56,57,58], (5) Y128 is in the center of HB-and-SB-network of HB(Y128-D178), SB(D178-R164), HB(Y128-R164), HB(Y128-H177), HB(H177-N154) [59,60,61,62], (6) A133 and S132 have HBs with R220 and a water binding site with G131 [63,64], in PrP(113-132) the hydrophobic cluster with vdWs rendering of atoms in residues 113-127 interacts with the first β-strand (see Figure 2(B) of [65]), M129 makes interactions with the side chain of V122 and pulls the N-terminus into the β-sheet [61] and M129 is very close to Y163 [31], (7) conservation of the Gly-rich region PrP(119-131) is required for uptake of prion infectivity [3,66,67] is shown by the physical or chemical properties of numerous mutations in the PrP(119-131) Gly-rich region [3], (8) one O-linked sugar at Ser135 can affect the coil-to-β structural transition of the prion peptide, but at Ser132 the effect is opposite [68], etc., and (9) the NMR structure of HuPrP(110-136) in dodecylphosphocholine micelles was known (2LBG.pdb) [69] and we do MD simulations for it as follows.…”

Glycosaminoglycan sulfation determines the biochemical properties of prion protein aggregates

“…Heparin and HS have also been shown to induce and accelerate oligomeric and fibrillar complex formation upon their addition to PrP peptides (Gonzalez-Iglesias et al 2002;Boshuizen et al 2007;Bazar and Jelinek 2010;Di Domizio et al 2012). GAGs, including PPS, HS and HSPG, have been investigated as cofactors in the conversion of PrP C to PrP Sc in cell free conversion assays and have been shown to both enhance or have no effect on the conversion process (Wong et al 2001;Ben-Zaken et al 2003;Deleault et al 2005;Lawson et al 2010;Klemm et al 2012). This may be because many factors influence PrP-GAG interactions including the degree of GAG sulfation and overall size of the GAGs (Gabizon et al 1993;Ben-Zaken et al 2003;Ouidja et al 2007;Lawson et al 2010;Monsellier et al 2010).…”

In vitro Modeling of Prion Strain Tropism

“…It was suggested that in vitro conversion using a hamster substrate was mostly dependent on the availability of PrPc. However, it was not confirmed in a study using grey and white matter of the same sample [75]. Moreover, it was shown that a high level of PrPc expression does not systematically correlate with a high conversion rate.…”

“…This suggests that RNAs are not essential cofactors that influence brain targeting by human prion strains. Other cofactor candidates include metal ions [64], glycosaminoglycans [84], laminin receptor (LRP/LR) [85,86,87], and anionic lipids [61,75]. For example, poly-anionic cofactors affected the strain specificity of infectious recombinant prions generated in vitro [88].…”