Human Prion Disorders Research Articles

Therapeutic approaches for prion disorders

Prion diseases are lethal for both humans and animals, and affected individuals die after several months following a rapid disease progression. Although researchers have attempted for decades to develop effective therapeutics for the therapy of human prion disorders, until now no efficient drug has been available on the market for transmissible spongiform encephalopathy (TSE) treatment or cure. Approximately 200 patients worldwide have died or suffer from variant Creutzfeldt–Jakob disease (CJD). Incidences for sporadic and familial CJD are approximately 1.5–2 per million per year and one per 10 million per year, respectively, in Europe. This review summarizes classical and modern trials for the development of effective anti-TSE drugs, introduces potential effective delivery systems, such as lentiviral and adeno-associated virus systems for antiprion components, including antibodies and siRNAs, and presents vaccination trials. Most of the antiprion drugs target prion protein PrPc and/or PrPSc. Alternative targets are receptors and coreceptors for PrP, that is, the 37/67-kDa laminin receptor and heparan sulfate proteoglycanes. We review clinical trials for the treatment of TSEs and describe hindrances and chances for a breakthrough in therapy of prion disorders.

Novel Prion Protein Conformation and Glycotype in Creutzfeldt-Jakob Disease

To describe a novel molecular and pathological phenotype of Creutzfeldt-Jakob disease. Patient A 69-year-old woman with behavioral and personality changes followed by rapidly evolving dementia. Postmortem examination of the brain showed intracellular prion protein deposition and axonal swellings filled with amyloid fibrils. Biochemical analysis of the pathological prion protein disclosed a previously unrecognized PrP(Sc) tertiary structure lacking diglycosylated species. Genetic analysis revealed a wild-type prion protein gene. The prion agent responsible for this atypical phenotype was successfully passaged to bank voles. To our knowledge, our results define a new human prion disorder characterized by intracellular accumulation of a novel type of pathological prion protein.

Sporadic Creutzfeldt-Jakob disease: further twists and turns in a convoluted protein

Sporadic Creutzfeldt–Jakob disease (sCJD) is the commonest form of human prion disease, with an annual mortality rate of ∼1–1.5 million cases per annum in most countries where systematic surveillance has been established (Ladogana et al ., 2005). The combined data from these studies have allowed analysis of hundreds of cases of this rare disease, as shown by Collins and colleagues, in this issue of Brain (Collins et al ., 2006). The phenotypic spectrum of sCJD is broad, including several clinical subgroups that have been recognized for many years, amongst which are the Brownell–Oppenheimer and Heidenhain variants. The basis of this clinicopathological variation in sCJD has been studied for over 10 years, with the general consensus that the two major phenotypic determinants are the presence of either methionine or valine at the polymorphic codon 129 of the patient's prion protein gene ( PRNP ), and the physico-chemical properties of the abnormal prion protein (PrPSc) that accumulates in the brain during the course of the disease (Ironside et al ., 2005). The former is readily and unambiguously determined by restriction length polymorphism analysis or gene sequencing, but the latter is generally approached indirectly by determining the size of the protease resistant core fragment of the PrPSc by western blotting of detergent-extracted and proteinase K-digested homogenates of CJD brain tissue. Two rival classification systems for the PrPSc isoforms accumulating in the brain in sCJD and other human prion disorders exist (Parchi et al ., 1999, Hill et al ., 2003). Although much has been made of their differences, a neutral observer would be struck by the considerable extent of overlap between the two systems. The Hill et al . (2003) system recognizes three PrPSc size classes, whereas two major classes (with subtypes) are recognized by Parchi et al . (1999) …

Immunoquantitative PCR for Prion Protein Detection in Sporadic Creutzfeldt–Jakob Disease

The most common human prion disorder is Creutzfeldt-Jakob disease (CJD); it includes sporadic, familial, iatrogenic, and variant subtypes. Diagnostic tests aim at detection with the highest specificity of very small deposits of abnormal prion protein (PrP). We used immunoquantitative PCR (iqPCR) to detect proteinase K-resistant PrP (PrPRes) in tissue from the middle frontal gyrus of 7 patients with sporadic CJD and 7 non-CJD cases. We compared iqPCR with routine optimized ELISA, Western blotting, and immunohistochemical analyses. The 4 methods showed similar 100% sensitivity and specificity for the diagnosis of CJD. Along with high specificity, however, iqPCR had a threshold for PrP(Res) detection at least 10-fold lower than that of the classic ELISA. iqPCR is a new method for PrPRes detection that combines 100% specificity with a detection threshold at least 10-fold lower than classic techniques. This method may improve the detection of minute PrPRes deposits in tissues and body fluids and thus be useful for diagnostic and sterilization applications.

Migration of dendritic cells into the brain in a mouse model of prion disease

The immune system plays a key role in the dissemination of prion infections from the periphery to the central nervous system (CNS). While follicular dendritic cells are critical for prion replication in lymphoid tissue and subsequent neuroinvasion, myeloid dendritic cells (DCs) have been implicated in both the clearance and propagation of pathological prion protein. Since nothing is known on the ability of DCs to migrate to the CNS during prion diseases, we investigated the immunohistochemical localization of CD205 + DCs in the brain of C57BL/6 mice intraperitoneally infected with the mouse-adapted KFu strain of Gerstmann–Sträussler–Scheinker syndrome, a human genetic prion disorder. In normal brain, CD205 + cells were present in the meninges and choroid plexus, whereas in the majority of mice sacrificed between 120 and 300 days post infection, CD205 + DCs were also detected in the cerebral cortex, subcortical white matter, thalamus and medulla oblongata. These findings demonstrate that DCs can enter the CNS of prion-infected mice, suggesting a possible role for these cells in the pathogenesis of prion disorders.

Therapeutic approaches in treating Creutzfeldt-Jakob disease – what does the future hold?

Creutzfeldt-Jakob disease (CJD) is one of the human prion disorders. It has a rapid disease course and is invariably fatal. Currently, no therapy is available. The causative agent is thought to be the prion protein, which acquires a pathological isoform through a conformational change and is hardly degradable. Experimental research has identified several substances, which were able to modestly inhibit the formation and propagation of pathological prion configurations. However, these substances were only effective when administered around the time of inoculation with the pathological prion. This review discusses the possibilities and limitations encountered in the development of pharmacotherapeutics for CJD.

Prion disease: Possible implications for oral health care

Prion diseases are a group of rare fatal neurodegenerative disorders in humans and animals that are histopathologically characterized by spongiform change within the central nervous system. The author reviewed all available case reports and any studies of the oral aspects of prion diseases published in peer-reviewed journals and available via PubMed. He then outlined the risk of nosocomial transmission of prions in dental health care. Sporadic Creutzfeldt-Jakob disease, or sCJD, is the most common of the acquired human prion disorders, and it typically affects elderly people and leads to rapid death. In contrast, variant CJD, or vCJD, has affected young adults from Europe, giving rise to a slow onset disorder comprising both psychiatric and neurological upset. Oral neurological manifestations are rare and seem to occur only in people with vCJD; there are no oral mucosal or gingival manifestations of prion disease. Prions can be detected in the oral tissues--usually the gingivae and dental pulp--of animals experimentally infected with prions. In contrast, prions have not been detected in the pulpal tissue of people with sCJD, and there are no data of pulpal infection in vCJD. There also are no data suggesting that prions are transmitted easily in the dental setting, but there remains the rare risk of such transmission if appropriate infection control measures are not adhered to. Few people in the United States and worldwide have prion disease. Oral manifestations are rare. Evidence suggests that the risk of transmission and acquisition of a prion infection as a result of dental treatment is rare, if appropriate infection control measures are maintained.

Prion diseases.

Prion diseases are incurable neurodegenerative conditions affecting both animals and humans. They may be sporadic, infectious, or inherited in origin. Human prion diseases include Creutzfeldt-Jakob desease (CJD), Gerstmann-Straussler-Scheinker disease, kuru, and fatal familial insomnia. The appearance of variant CJD, and the demonstration that is caused by strains indistinguishable from bovine spongiform encephalopathy (BSE) in cattle, has led to the threat of a major epidemic of human prion disease in the UK and other countries where widespread dietary exposure to bovine prions has occurred. This article reviews the history and epidemiology of these diseases, and then focuses on important areas of current research in human prion disorders.

NEUROLOGICAL ILLNESS IN TRANSGENIC MICE EXPRESSING A PRION PROTEIN WITH AN INSERTIONAL MUTATION

Familial prion diseases are caused by mutations in the gene encoding the prion protein (PrP). We have produced transgenic mice that express the mouse homolog of a mutant human PrP containing a nine octapeptide insertion associated with prion dementia. These mice exhibit a slowly progressive neurological disorder characterized clinically by ataxia and neuropathologically by cerebellar atrophy and granule cell loss, gliosis, and PrP deposition that is most prominent in the cerebellum and hippocampus. Mutant PrP molecules expressed in the brains of these mice are resistant to digestion by low concentrations of proteinase K and display several other biochemical properties reminiscent of PrP(Sc), the pathogenic isoform of PrP. These results establish a new transgenic animal model of an inherited human prion disorder.

Neurological Illness in Transgenic Mice Expressing a Prion Protein with an Insertional Mutation

Familial prion diseases are caused by mutations in the gene encoding the prion protein (PrP). We have produced transgenic mice that express the mouse homolog of a mutant human PrP containing a nine octapeptide insertion associated with prion dementia. These mice exhibit a slowly progressive neurological disorder characterized clinically by ataxia and neuropathologically by cerebellar atrophy and granule cell loss, gliosis, and PrP deposition that is most prominent in the cerebellum and hippocampus. Mutant PrP molecules expressed in the brains of these mice are resistant to digestion by low concentrations of proteinase K and display several other biochemical properties reminiscent of PrP Sc, the pathogenic isoform of PrP. These results establish a new transgenic animal model of an inherited human prion disorder.

New variant Creutzfeldt-Jakob disease.

New variant Creutzfeldt-Jakob disease is a novel human prion disorder with characteristic clinical and neuropathological features, which results from exposure to the bovine spongiform encephalopathy agent. The probably lengthy incubation period makes it difficult to predict future new variant Creutzfeldt-Jakob disease case numbers; further studies are required to clarify risk factors and the potential for human spread.

Sulfated glycosaminoglycans in amyloid plaques of prion diseases

Brain sections from cases of human Creutzfeldt-Jakob disease, Gerstmann-Sträussler syndrome, kuru, and hamster scrapie containing amyloid were examined for the presence of sulfated glycosaminoglycans (GAGs), the anionic component of proteoglycans, using the sulfated Alcian blue method and Alcian blue technique with 0.3 M and 0.7 M magnesium chloride. These studies suggest that sulfated glycosaminoglycans are part of the CNS amyloid plaques in each of the above human prion disorders as well as in experimental scrapie. All the amyloid plaques stained positively with Alcian blue at 0.3 M, and less so at 0.7 M magnesium chloride indicating the presence of sulfated GAGs. Therefore, the amyloid plaques of prion diseases possess similar histochemical features to those found in Alzheimer's disease.