Prion, pathogenic

As summarized by Bultman et al. (in press), a number of soil-borne pathogens have been linked to a variety of diseases, including protozoa, bacteria, fungi, viruses, and prions. Pathogens considered to be soil-borne include those that complete all or some of their life cycles in soils, and those whose life cycle is spent primarily in other organisms but that can survive for some period of time if released into soils from their hosts. Depending upon the particular pathogen, exposure can result from inhalation of dusts... 

Pathogenic mutations in the prion protein gene cause inherited prion disease 793... 

How pathogenic mutations in PRNP cause prion disease has yet to be resolved. However, in most cases the mutation is thought to lead to an increased tendency of PrPc to form PrPSc, although there is evidence to suggest that this may not be solely attributable to decreased thermodynamic stability of mutated PrPc. Experimentally manipulated mutations of the prion gene can lead to spontaneous neurodegeneration without the formation... 

Subclinical or carrier states of prion disease have major implications for public health, most notably iatrogenic transmission from apparently healthy individuals. The existence of subclinical prion infections also raise the possibility that other species (such as sheep, pigs and poultry), exposed to BSE prions by contaminated feed, might be able to develop subclinical carrier states. Given that BSE prions are pathogenic in a wide variety of species, and that the strain characteristics of BSE prions are retained upon transmission to new species, it must be considered possible, if not probable, that BSE in animals other than cattle will retain pathogenicity for humans. 

Infection by PrPSc is a more challenging—and obscure—process. Pathogens in mammals not only have to spread within an infected organism but also they must spread from one organism to another. The route of transmission followed by PrPSc is more complicated than that of fungal prions and places more requirements on this system. Tissues other than brain are also involved (Aguzzi, 2003 Seeger et al., 2005). 

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. 

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,... 

Several NMR studies were carried out to gain insight into the molecular basis for the conversion of the PrP " into the pathogenic conformer, PrP . They mainly involve the study of prion-derived peptides believed to be essential for prion propagation, although other studies also include the investigation of the whole prion protein ° and prion mutants. 

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. 

Pan Y, Chefalo P, Nagy N, Harding C, Guo Z. Synthesis and immunological properties of W-modified GM3 antigens as therapeutic cancer vaccines. J. Med. Chem. 2005 48 875-883. Rudd PM, Endo T, Colominas C, Groth D, Wheeler SF, Harvey DJ, et al. Glycosylation differences between the normal and pathogenic prion protein isoforms. Proc. Natl. Acad. Sci. U.S.A. 1999 96 13044-13049. 

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