Creutzfeldt-Jacob Disease In Humans Research Articles

Asynchronous Onset of Clinical Disease in BSE-Infected Macaques

To estimate the effect of the variability of prion disease onset on primary bovine spongiform encephalopathy transmission to humans, we studied 6 cynomolgus macaques. The preclinical incubation period was significantly prolonged in 2 animals, implying that onset of variant Creutzfeldt-Jacob disease in humans could be more diverse than previously expected.

Species variation in PrPSc protofibril models

The misfolding and aggregation of the prion protein (PrP) is the primary cause of a group of infectious neurodegenerative diseases including Creutzfeldt-Jacob disease in humans and Bovine Spongiform Encephalopathy in cows. A single disease can exhibit different infectious strains distinguishable by incubation time and morphology or distribution of the aggregates. Infected brain tissue from one species can be used to infect other species, but with different efficiencies, suggesting a spectrum of species compatibility. If PrP is, as widely believed, the sole component of infection, then the species and strain differences must be accounted for by the structure of the aggregates, likely influenced by each species’ PrP sequence. As there are no high-resolution data exploring this hypothesis, we performed molecular dynamics simulations of PrP for human, bovine, hamster, and D147N mutant hamster sequences at low pH to induce misfolding of the protein. We selected representative converted structures from each of the four sequences and, with the guidance of experimental data, constructed models of the infectious aggregates. Both hamster monomers showed high flexibility during conversion, suggesting hamster may more easily adopt altered conformations, which in turn may explain why it is more easily infected by some other species. Human and bovine aggregates were similar, with monomers docking in P31 symmetry to form a left-handed spiral. In contrast, hamster aggregates formed a P31 right-handed spiral. We detail the differences in the converted monomers that give rise to this difference and show that our results compare favorably with experimental data.

Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform Encephalopathy Prion Strain

Bovine spongiform encephalopathy (BSE), the prion disease in cattle, was widely believed to be caused by only one strain, BSE-C. BSE-C causes the fatal prion disease named new variant Creutzfeldt-Jacob disease in humans. Two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H, have been discovered in several countries since 2004; their transmissibility and phenotypes in humans are unknown. We investigated the infectivity and human phenotype of BASE strains by inoculating transgenic (Tg) mice expressing the human prion protein with brain homogenates from two BASE strain-infected cattle. Sixty percent of the inoculated Tg mice became infected after 20 to 22 months of incubation, a transmission rate higher than those reported for BSE-C. A quarter of BASE strain-infected Tg mice, but none of the Tg mice infected with prions causing a sporadic human prion disease, showed the presence of pathogenic prion protein isoforms in the spleen, indicating that the BASE prion is intrinsically lymphotropic. The pathological prion protein isoforms in BASE strain-infected humanized Tg mouse brains are different from those from the original cattle BASE or sporadic human prion disease. Minimal brain spongiosis and long incubation times are observed for the BASE strain-infected Tg mice. These results suggest that in humans, the BASE strain is a more virulent BSE strain and likely lymphotropic.

Identification of β-aggregate sites in protein chains

The problem of amyloidoses is pressing and have recently attracted special attention throughout the world because of epidemics of prion diseases such as mad cow disease and human Creutzfeldt-Jacob disease. These diseases result from the conversion of a native protein or peptide into a highly stable pathological form. Molecules having a pathological conformation aggregate to form amyloid fibrils, capable of unlimited growth. It is important to study the molecular mechanisms of prion diseases and to identify the protein regions responsible for their development. The review considers theoretical and experimental works focusing on the formation of amyloid fibrils.

Single nucleotide polymorphisms of the prion protein gene (PRNP) in Chinese pig breeds

Prion diseases (transmissible spongiform encephalopathies, TSE), as a group of fatal neurodegenerative diseases, have affected humans and a variety of other mammals. Although no natural TSE have been documented in pigs, appropriate precautions need to be taken to prevent the iatrogenic spread of prion disease through pig-to-human xenotransplantation. Polymorphisms within the open reading frame (ORF) of the single-copy gene of prion protein (PRNP) are associated with susceptibility to scrapie in sheep and variant Creutzfeldt-Jacob disease in humans. We screened polymorphisms in the PRNP gene of 64 China Experimental Minipigs and Beijing Large White pigs. Our findings suggest that the porcine PRNP gene is highly homogenous. The amino acid sequences of the mature prion protein of all samples tested were identical. Four single nucleotide polymorphisms (G11A, G615C, G684A, T726G) in the ORF of the porcine PRNP gene were found, and the G-->C nucleotide substitution resulted in a serine to asparaginate amino acid substitution at codon 4. We conclude that pigs raised under specific pathogen-free conditions, with the exclusion of rendered mammalian material for at least two generations, will have little risk of being infected with a TSE, and even less possibility of transmitting prion disease to humans through xenotransplantation.

Transmissible spongiform encephalopathies--anesthesiologic and intensive care management

The transmissible spongiform encephalopathies (TSE) are known to affect humans and various animals. The bovine spongiform encephalopathy (BSE) and the human Creutzfeldt-Jacob disease (CJD) are among the most notable degenerative disorders caused by prions. Considering the BSE epidemic and the description of a new variant of Creutzfeldt-Jacob disease (nvCJD), which is probably related to bovine spongiform encephalopathy, TSE have recently gained a lot of public attention. Although the causative factors (prions, viruses) are still under discussion, none of the present concepts are explanatory for all aspects of the human CJD. CJD may present as a sporadic, genetic, or infectious illness and there is now considerable concern that bovine prions may have been passed to humans. To exclude transmission of CJD via medical products and instruments, the effectiveness of cleaning, disinfection and sterilization procedures must be firmly established. This manuscript presents an overview to anaesthesiology and intensive care medicine of recommended inactivation procedures and assessed these procedures in the light of the inactivation of prions.

Ovine scrapie: priorities and importance.

Ovine and caprine scrapie occupies a unique place among animal transmissive spongiform encephalopathies (TSE). It is an object of intensive biomedicinal, ecological and economical studies. Its causative agents are demonstrably associated with the development of TSE in farmed minks, goats and moufflons. Ovine strains of scrapie occurring in North America (particularly in the USA) differ from strains which occur in Europe and were present at the onset of development of TSE in three species of deer living in free nature and in captivity in the USA. The studies dealing with the development of bovine spongiform encephalopathy (BSE) of the English type have indicated justifiably that its origin is associated with one (or more) heretofore unidentified ovine strain. The development of a variant form, the Creutzfeldt-Jacob disease in humans, and transmission of the BSE agent to several families of bovidae, felidae and primates, puts stress on its zoonotic potential. All this leads to the conclusion that domesticated sheep are the decisive reservoir species of animal TSE. They have been infected to an unknown extent with the causative agent of BSE probably through contaminated meat-bone meal. The occurrence of natural ovine prion isolates with properties similar to those of the BSE agent requires that scrapie should be included in the surveillance of human and animal TSE. At present, scrapie is a noticeable disease also in other than European Communities Member States. It is on the list B of the International Epizootics Office. Many countries have initiated control of ovine scrapie. It should therefore become a topical question also in Central and Eastern European countries. Elimination or even eradication of ovine scrapie (or its causative agents) from populations of small and large domestic ruminants is the prerequisite for prevention of penetration of ovine pathogenic prions into the human feed chain. Moreover, it should be ensured that these species will be able to produce foods of a new type (immunotrition and similar) or proteins with therapeutic effects in the near future. Our study established that the PrP genotype of Valachian rams, the Slovak autochthonous breed, contains also VRQ and ARQ alleles encoding the susceptibility to scrapie. Their selection is part of the improvement of Slovak Valachian sheep towards resistance to scrapie.

Functional integrity of benzodiazepine receptors of the geniculo-striate visual pathways in Creutzfeldt-Jakob disease

We evaluated the effects of flumazenil (FMZ), a high-affinity benzodiazepine receptor antagonist, on flash-evoked visual potentials (FEPs) in a patient with Creutzfeldt-Jacob disease (CJD). FEPs were recorded in three different consecutive sessions: (1) basal condition, without any pharmacological treatment; (2) 3.5 min after i.v. administration of 5 mg FMZ; (3) 1 min after i.v. administration of 10 mg diazepam (DZP). FMZ provoked a marked increase in the amplitude as well as evident shortening of the latency of early FEP components. DZP reversed these effects. These results are in agreement with our previous findings of anatomical and functional integrity of the geniculo-striate pathways in human CJD and demonstrate functional integrity of benzodiazepine receptors in this visual system in CJD.