Protein only hypothesis

A key feature of the protein-only hypothesis is that variants should represent distinct structural forms of the prion protein. A direct connection between filament structure and variants was made by Tanaka et al. (2004) using filaments made under different conditions (in this case, 4°C and 37°C). Filaments formed at 4°C were less stable against heating in 1.6% SDS and gave rise mostly to strong [PSI] variants after being transformed... 

Protein only" hypothesis for prion plaque formation,... 

Keywords Creutzfeldt Jakob disease Fatal insomnia Gerstmann-Straussler-Scheinker Kuru Neuroinvasion Prion Protein-only hypothesis. 

TSEs can exhibit inherited, infectious and sporadic presentations. Additionally, the inherited disease can also be infectious. CJD occurs both as an inherited autosomal dominant disorder and in a transmissible form. In the protein only hypothesis, the abnormal prion protein, either introduced from external sources or produced by the mutated prion protein gene, affects normal protein folding and shifts the prion protein folding towards the formation... 

Like other neurodegenerative disorders, such as Alzheimer s and Parkinson s disease, prion diseases are characterized by the formation and accumulation of an aberrantly folded protein in the brain. However, a unique feature of prion diseases is their transmissibility. Prions (acronym for proteinaceous infectious particles) are mainly composed of PrPSc, polysaccharides, and lipids, but lack nucleic acids longer than 25 nucleotides, arguing against an essential role for DNA/RNA in mediating infectivity [35, 36]. Indeed, recent experiments support the protein-only hypothesis recombinant PrP expressed in and purified from bacteria and subsequently misfolded in vitro can transmit the disease [37-40]. 

The central dogma of molecular biology has traditionally posited that nucleic acids alone function as genetic determinants because these macromolecules can template their own replication. The prion or protein-only hypothesis expands the central dogma to include proteins as etiologic agents for disease transmission (Griffith, 1967 Prusiner 1982) and elements of inheritance for phenotypic traits (Wickner, 1994). Prions are unique proteins that can exist in more than one stable conformation, and at least one of these states can be transmitted to newly synthesized protein as a form of templated replication. Since each physical state is associated with a distinct phenotypic state, the trait becomes heritable. 

The complete reversibility of unfolding of PrP(121-231), PrP(90-231) and PrP(23-231) has principal implications within the framework of the protein only hypothesis if one extrapolates the results from the recombiant proteins to natural PrP. If PrP and PrP indeed have identical covalent stuctures (Stahl and Prusiner, 1991), both PrP and PrP will yield identical unfolded forms in the presence of high concentrations of the denaturants urea and GdmCl. This predicts that, after reconstitution in vitro, one would always obtain folded PrP, independent of whether the experiment was started from PrP or PrP . This would explain why all attempts to reconstitute infectivity after complete solubilization of infectious PrP with high concentrations of GdmCl or urea have failed (Prusiner et al, 1993). 

The fact that all forms of inherited human prion diseases known so far are linked with dominant mutations in the gene encoding human PrP has been used as a strong argument in favor of the protein-only hypothesis, as the infectious prion agent spontaneously develops in affected individuals (for reviews, see Prusiner, 1997 Prusiner et al,... 

Nonetheless, this cell-free assay conversion of recombinant protein provides strong evidence for the protein-only hypothesis, but demonstration of true infectivity of the converted material is still necessary. Furthermore, DebBurman et al (1997) have shown that GroEL, a known protein-folding chaperone, increases the efficiency of conversion in the cell-free assay but only in the presence of PrP . ... 

The protein-only hypothesis indicates that the scrapie form of the prion protein can promote the conversion of the cellular form. This leads to the conclusion that prions themselves can act as chaperones (Liautard, 1991). Thermokinetic analysis of protein folding shows that a misfolded chaperone gives rise to new misfolded chaperones, which fit very well to the protein-only hypothesis in which PrP triggers the formation of PrP. ... 

According to the protein-only hypothesis, proposed by Prusiner (Fig. 5), the interaction of the cellular prion protein with the pathological isoform seems to be the crucial step in the conversion of PrP = to PrP . The existence of the hypothetical PrP =/PrP heterodimer may require the presence of a homodimer consisting of two PrP = molecules. This homodimer is thought to be in equilibrium with the PrP monomers. It is unclear to date wether the spontaneous conversion reaction involves PrP monomers or the PrP homodimers. 

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