Scrapie disease prion

The potential for presymptomatic detection of prions in the blood of infected individuals has profound importance for humans exposed, or potentially exposed, to contaminated food. Saa et al. (2006) show that the scrapie disease prion (PrFO can be detected biochemically in the blood of scrapie-infected hamsters during most of the presymptomatic phase of the disease. Infectious prions have also been found in the blood of CWD-positive deer (Mathiason et al., 2006). Because the human population may have been seeded with vCJD disease as a result of the BSE epidemic, the potential to detect prions in presymptomatic individuals would seem to have profound importance for human blood donation and organ transplantation, as well as for the screening of farm and game animals. The potential for development of immunity (Peretz et al., 2001 Heppner et al., 2001 Pankiewicz et al., 2006) or of effective vaccines (Sadowski and Wisniewski, 2004) may open the door to effective management or cure, which are at present out of reach. 

Alzheimer s disease, Parkinson disease, prion diseases (Creutzfeld-Jacob in humans, scrapie in sheep), Huntington disease, dementia with Levy s bodies, sclerosis multiplex and amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and vascular dementia are the most commonly occurring neurodegenerative diseases, with different (and often unknown) pathophysiology, creating serious health care problems and... 

Keywords Animal Atypical Atypical/Nor98 scrapie BSE-H BSE-L Human Prion disease Prion strain Prion type... 

Prion and scrapie diseases are linked with the conformational transition of normally monomeric a-helical cellular prion protein, PrP, to a B-sheet-rich pathogenic form, PrP , which is prone to aggregation. A similar conformational transition of the normal cellular form of a-helical amyloid peptide (aAP (1-40)) into the disease-specific largely B-sheet form of amyloid peptide (BAP (1-40)) occurs in Alzheimer s disease, which results in amyloid deposits (Monaco et al., 2006). So far more than 19 different mutations in the human PrP gene have been linked with inherited prion diseases (Monaco et al., 2006). However, the molecular event triggering the spontaneous conversion of wild-type and... 

However, it appears that not all TSEs are transferable to all species. Scrapie disease in sheep is not known to be infectious in humans, although it seems infectious in cows. Thus, there appear to be species barriers to infectivity. The potential infectivity of CWD disease to humans is not known, although testing of game animals taken by hunters in the CWD-infected areas has been encouraged. The mechanism for the horizontal spread of CWD in deer and elk is without explanation, and it is not clear if transmission to humans is possible, or what the disease would look like if it were transmitted (Xie et al., 2006). It is intriguing to speculate that prion infectivity could leap from one species to another nonpermissible species by way of a permissible intermediate, possibly as evidenced by sheep scrapie to mad cow to human vCJD. 

As more infectious prions are created, they aggregate together into fibrils, and it is these fibrils that appear to induce disease. Prions are the cause of a number of degenerative brain diseases, including bovine spongiform encephalopathy or mad cow disease in cattle, scrapie in sheep and goats, chronic wasting disease in the wild cervids (the deer, moose, and elk), and Creutzfeldt-Jakob disease in humans. 

The transmissible spongiform encephalopathies, or prion diseases, are fatal neurodegenerative diseases characterized by spongiform changes, astrocytic gliomas, and neuronal loss resulting from the deposition of insoluble protein aggregates in neural cells. They include Creutzfeldt-Jakob disease in humans, scrapie in... 

Prions—protein particles that lack nucleic acid— cause fatal transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease, scrapie, and bovine spongiform encephalopathy. Prion diseases involve an altered secondary-tertiary strucmre of a namrally occurring protein, PrPc. When PrPc interacts with its pathologic isoform PrPSc, its conformation is transformed from a predominantly a-helical strucmre to the P-sheet strucmre characteristic of PrPSc. 

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. 

The prion diseases are a closely related group of neuro-degenerative conditions which affect both humans and animals. They have previously been described as the subacute spongiform encephalopathies, slow virus diseases and transmissible dementias, and include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and the human prion diseases, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and kuru. Prion diseases are... 

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. 

Creutzfeldt-Jakob and other prion diseases have been associated with disorders of copper metabolism. The first cases of Creuzfeldt-Jakob disease in humans were described by Creuzfeldt and Jakob over 80 years ago. Although scrapie was known as a fatal neurological... 

Fig. 20 Fluorescent images of prion deposits associated with distinct prion strains, murine chronic wasting disease (mCWD) (a) and murine sheep scrapie (mSS) (b), which has been stained by PTAA. (c) Correlation diagram of the ratios, R532/639 and R532/ max, of the intensity of the emitted light from PTAA bound to prion deposits originating from individual mice infected with CWD (black symbols) or sheep scrapie (purple symbols) [35]...

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,... 

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... 

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