Prion proteins infectious

Amyloid aggregates of the HET-s prion protein are infectious. Proc. Natl. Acad. Sci. USA 99, 7402-7407. 

The abnormal deposits found in the brains of CJD victims consist of an abnormal isoform of PrP. Prion protein is normally found in cells. Detailed structural studies show that normal cellular PrP (PrP ) is a soluble protein whose conformation is rich in a-helices with very little P-sheet. The PrP protein extracted from the brains of CJD victims (i.e., PrP ) is identical in primary amino acid sequence to the normal PrP (PrP ). However, PrP has a much greater content of P-sheet conformation with little a-helical structure. Thus PrP is neurotoxic because of its three-dimensional structure. When the prion protein is predominantly in an a-helical conformation it is nontoxic when the prion protein is predominantly in a P-sheet conformation, it kills neurons. The prion protein is thus made neurotoxic not by its amino acid composition but by its conformation. This concept is both fascinating and terrifying. Prion diseases are transmissible thus prions are infectious agents. However, prions are not like bacteria or viruses, or other infectious microbes—they are simply protein molecules. Prions are not microbes with cell membranes and nucleic acids they are not living things. Indeed, prions are not even infectious molecules, they are infectious molecular shapes. 

The prion protein (PrP) is an infectious protein that converts noninfectious PrP into the infectious form, which precipitates. PrP is implicated as the causative agent of the transmis sible spongiform encephalopathies, including Creutzfeld-Jakob disease. 

EMPs as Carriers of Molecules. In addition to measurable antigens, EMPs as other MPs, are also carriers of molecules. Conformationally changed prion proteins, believed to aid in the propagation of spongiform encephalopathies, have been detected on EMPs released by infected ECs [68]. This finding indicates that EMPs may be active players in the infectious process of spongiform encephalopathies. 

In 2001, the antimalarial drug quinacrine and the antipsychotic drug chlorpro-mazine (Fig. 1.14) were shown to inhibit prion infection in cells. Pmsiner and coworkers [24] identified the drugs independently, and found that they inhibited the conversion of normal prion protein into infectious prions, and also cleared prions from infected cells. Both drugs can cross over from the bloodstream to the brain, where the prion diseases are localized. 

The most widely accepted theory of prion diseases suggests that the infectious prion protein has the same primary structure as a normal protein found in nerve cells, but it differs in its tertiary structure. In effect, it is a misfolded, denatured version of a normal protein that polymerizes to form the amyloid protein plaques seen in the brains of infected animals. When an animal ingests infected food, the polymerized protein resists digestion. Because it is simply a misfolded version of a normal protein, the infectious prion does not provoke the host s immune system to attack the pathogen. 

This group of diseases is characterized by the accumulation of a specific isoform of the normal prion protein (PrP), termed PrPSc, which seems to be the main infectious agent. PrPSc is derived by a conformational change from the isoform of the prion protein PrPC. PrPSc is a copper-binding glycoprotein attached to the cell membrane of neuronal cells [21]. The PrPSc form is protease resistant, has a beta-sheet structure and possesses a tendency to polymerization [22]. 

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... 

With the high spatial resolution of the synchrotron, individual cells within a tissue can be probed with subcellular resoluhon. For example, the structures of misfolded protein aggregates in neurological protein folding diseases have been identified in the brain tissue of Alzheimer s disease patients [31-33], while infectious prion proteins have been characterized in scrapie [34-37]. Additional biochemical changes have also been observed in the fingerprint regions of Alzheimer s [38], Parkinson s [39] and scrapie-infected tissues [40]. 

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