Prion scrapie form

With the background of the mad cow crisis in Europe, questions relating to the prion diseases have attracted intensive interest. It is now widely accepted that prion diseases, such as Creutzfeldt-Jakob disease (CJd) in humans and bovine spongiform encephalopathy (BSE) are caused by a conformational change of the prion protein (PrP) from a normally folded cellular form, PrP ", to an alternate, aggregation-prone, pathogenic scrapie form,... 

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. ... 

Soto, C. 2006. Prions. The New Biology of Proteins. CRC Press, Boca Raton, USA Stahl, N., Borchelt, D. R., and Prusiner, S. B. 1990. Differential release of cellular and scrapie prion protein form cellular membranes of phosphatidylinositol specific phospholipase. Biochemistry 29 5405-5412... 

A prion protein, designated as PrP, has a natural monomeric form, designated PrP, and an insoluble, phase-separated or associated form, designated PrP , where the superscript C stands for the normal cellular form and the superscript Sc stands for the infectious scrapie form. PrP is degradable by proteoljdic enzymes, whereas PrP , the smaller component of PrP, forms a proteolytic resistant core. 

Kocisko DA, Priola SA, Raymond GJ, Chesebro B, Lansbury PT Jr, Caughey B. Species specificity in the cell-free conversion of prion protein to protease-resistant forms a model for the scrapie species barrier. Proc Natl Acad USA 1995 92 3923-3927. 

The conformational plasticity supported by mobile regions within native proteins, partially denatured protein states such as molten globules, and natively unfolded proteins underlies many of the conformational (protein misfolding) diseases (Carrell and Lomas, 1997 Dobson et al., 2001). Many of these diseases involve amyloid fibril formation, as in amyloidosis from mutant human lysozymes, neurodegenerative diseases such as Parkinson s and Alzheimer s due to the hbrillogenic propensities of a -synuclein and tau, and the prion encephalopathies such as scrapie, BSE, and new variant Creutzfeldt-Jacob disease (CJD) where amyloid fibril formation is triggered by exposure to the amyloid form of the prion protein. In addition, aggregation of serine protease inhibitors such as a j-antitrypsin is responsible for diseases such as emphysema and cirrhosis. 

It is still discussed in the literature whether so-called prion rods isolated from infectious brains (for which amyloid-like structure has been shown) correspond to the structure of the infectious form and/or the structure of the neurotoxic form of PrP. It is also under discussion whether filaments observed in diseased brains (so-called scrapie associated fibers) are similar to prion rods (reviewed in Weissmann, 2005). 

Fig. 3. Classification of human prion diseases. Sporadic the transformation from PrPc (circle) to PrPSc (square) occurs without apparent cause. Familial a point mutation ( ) is thought to facilitate the transformation. Infectious the transformation arises via PrPSc which acts as a template. The kinetic equations are defined by Eigen (1996). The infectious form includes kuru, iatrogenic CJD (iCJD), variant CJD (vCJD first reported in 1996), bovine spongiform encephalopathy (BSE first reported in 1985), and scrapie. In the nucleation-dependent model, monomeric PrPc and PrPSc are in chemical equilibrium.

The normal cellular form of prion protein (PrPc) can exist as a Cu-metalloprotein in vivo (492). This PrPc is a precursor of the pathogenic protease-resistant form PrPsc, which is thought to cause scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt—Jakob disease. Two octa-repeats of PHGGGWGQ have been proposed as Cu(II) binding sites centered on histidine (493). They lack secondary and tertiary structure in the absence of Cu(II). Neurons may therefore have special mechanisms to regulate the distribution of copper. 

Protein aggregation is a hallmark of scrapie, and scrapie protein can be induced to aggregate in vitro into forms that are indistinguishable from pathological brain-derived fibrils. Prusiner proposed that prion disease involves a mechanism for autocatalytic conversion of a host... 

Fig. 3 Folding pathway of prion protein to form scrapie. (From Ref.. )...

The misfolded form, scrapie, results in a class of disease called spongiform encephalopathies, e.g., mad cow disease. Unlike other diseases caused due to protein misfolding, prion diseases are infectious. The infecting agent is the misfolded protein. Prionogenic diseases are transmitted across the species barriers, from cow to sheep to human beings, and are fatal. 

Recently a serious public health problem has arisen by showing that a prion disease in cattle can cross species barriers and infect humans. This occurred when cattle were fed meal made from sheep infected with scrapie. The cattle developed BSE (commonly called mad cow disease ). Subsequently, when people consumed prion-contaminated beef, a small number, primarily in Great Britain, developed a variant of CJD (vCJD) approximately five years afterward. The variant form of CJD is a unique form of prion disease occurring in a much younger population than would be expected from inherited or sporadic CJD. Both BSE and vCJD share many similar pathologic characteristics suggesting an etiologic link between human vCJD and cattle BSE. 

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