Prion-based diseases

Kellershohn N, Laurent M. Species barrier in prion diseases a kinetic interpretation based on the conformational adaptation of the prion protein. Biochem J 1998 334 539-545. 

The use of a variety of techniques, ranging from classical drug design to genome-based drug design, will be required for a full and effective attack on the microbes of human disease, extending from simple prions to complex parasites. 

One such application of RSEs, or their constituent bond dissociation energies, is in the study of radical-mediated degradation mechanisms. For example, based on an examination of the relevant C-H and S-H bond dissociation energies in model peptides. Rank et al. postulated a mechanism for generating and propagating oxidative damage via a Met residue of the Ap peptide of Alzheimer s disease or the prion peptide of Creutzfeldt-Jakob disease. In a similar manner, Li et al. used C-H BDE calculations to identify the most vulnerable sites for radical-mediated damage in... 

The human prion diseases include CJD, kuru, Gerstmann-Straussler-Scheinker (GSS), and fatal insomnia, which can be classified into three groups based on etiology (Table 29.1). 

Among the human prion diseases, Pi-p " polypeptide fragments can vary in number (typically 1 to 3), molecular weight, and the ratio of the three glycoforms. Based on these criteria, Prps<" is classified into three operational groups called type 1, type 2 (a and b), and GSS-type (Table 29.2, Figure... 

The pattern of these prion diseases differs related to the pattern of PrPSc depositions, based on the occurring genotype of die prion protein and to the related different pathological conformer s of the PrPSc [21]. 

Percent of all human prion diseases based upon epidemiological data from Italy and Japan. 

What are the major types of human prion diseases based on clinical phenotypes ... 

SRM which include CNS tissue are tissues from animals that are known to carry, transfer, or perpetuate infectivity of the BSE causative agent, prions. Because BSE is an adult-onset disease, identification of tissues as SRM is dependent on the age of the animal at slaughter, and definitions of SRM vary by country, based on differences in interpretation of scientific evidence and the amount of risk allowed (Table 1). Care must be taken when removing SRM (including CNS tissue) to prevent contamination of products due to improper or incomplete removal of SRM and to prevent cross-contamination of SRM to meat products via personnel or equipment. 

Prions share the ability to propagate strain information with nucleic acid based pathogens, but it is unclear how they mutate and acquire fitness in the absence of this informational component. Because prion diseases occur as epidemics, understanding this mechanism is of paramount importance for implementing control strategies to limit their spread, and for evaluating their zoonotic potential. While the existence and mutability of strains persuaded early researchers that prion... 

Of particular interest are prion amplification assays that are capable of detecting prions in blood components such as plasma. However, blood typically has extremely low prion concentrations (i.e., 13 LD50 per mL [59]), and contains inhibitors of some of the most sensitive tests such as PMCA [19] and another assay [60]. Recently, we integrated antibody 15B3-based immunoprecipitation with QuIC reactions to increase sensitivity and isolate prions from inhibitors such as those in plasma samples [61]. Moreover, replacement of the rPrPc substrate after 24h in RT-QuIC reactions substantially improved the speed and sensitivity of the assay. Coupling of the immunoprecipitation and substrate replacement steps, which we call enhanced QuIC (eQuIC), dramatically enhanced detection of variant Creutzfeldt-Jakob disease (vCJD) brain tissue diluted into human plasma. 1014-fold dilutions, containing 2 ag/ml of proteinase K-resistant prion protein, were readily... 

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