Search

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are neurodegenerative diseases that affect many mammalian species. Some examples include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats, Creutzfeldt-Jakob [...]

In prion and Alzheimer's diseases, the roles played by amyloid versus nonamyIoid deposits in brain damage remain unresolved. In scrapie-infected transgenic mice expressing prion protein (PrP) lacking the glycosylphosphatidylinositol (GPI) membrane anchor, abnormal protease-resistant PrPres was deposited as amyloid plaques, rather than the usual nonamyloid form of PrPres. Although PrPres amyloid plaques induced brain damage reminiscent of Alzheimer's disease, clinical manifestations were minimal. In contrast, combined expression of anchorless and wild-type PrP produced accelerated clinical scrapie. Thus, the PrP GPI anchor may play a role in the pathogenesis of prion diseases., Transmissible spongiform encephalopathies (TSEs) or prion diseases (1) include CreutzfeldtJakob disease (CJD) in humans, bovine spongiform encephalopathy or 'mad cow dissease' in cattle, scrapie in sheep, and chronic wasting disease [...]

Fears about the transmission of bovine spongiform encephalopathy (BSE) to man were raised with the emergence of cases of of Creutzfeldt-Jakob disease (CJD), a human transmissible spongiform encephalopathy (TSE) in the UK. Experiments show a link between in vitro conversion efficiencies and and known BSE, sheep scrapie and CJD transmissibilities. An in vitro system was used to assess the possible transmissibility of BSE and scrapie to man, and a limited conversion of human PrP-sen to PrP-res was found. It was concluded that transmission to man following equivalent exposure is finite but low.

The study of species specificity in cell-free reaction combining the hamster protease sensitive form of prion protein (PrPc) with hamster protease-resistant isoform (PrPsc) and mouse PrPc with mouse PrPsc lead to the conversion of PrPc to Protease-resistant forms. The conversion of PrPc to protease-resistant forms was due to species specificity in the cell-free interactions which may be why scrapie and other transmissible spongiform encephalopathies are not transmitted between different species in vivo.

Protease-sensitive prion protein (PrPc) can be converted to protease-resistant forms that are analogous to scrapie-associated prion protein (PrPSc) in a cell-free system that contains purified components. This conversion is preferential and needs the presence of preexisting PrPSc, proving that PrPSc is obtained from specific PrPc-PrPSc interactions. The PrPSc formation mechanism is central in the transmissible spongiform encephalopathies pathogenesis.

The preparation of amyloid fibrils by using a pathogenic prion protein peptide which could be influenced to yield fibrils with novel ultrastructural properties by changing the physical microenvironment is presented.

The self-induced formation of the disease-associated, protease-resistant prion protein (PrP-res) from the normal protease-sensitive isoform (PrP-sen) appears to be a key event in the pathogenesis of transmissible spongiform encephalopathies. The amino acid sequence specificity of PrP-res formation correlates with, and may account for, the species specificity in transmission of transmissible spongiform encephalopathy agents in vivo. To analyze the mechanism controlling the sequence specificity of PrP-res formation, we compared the binding of PrP-sen to PrP-res with its subsequent acquisition of protease resistance by using cell-free systems consisting of heterologous versus homologous mouse and hamster PrP isoforms. Our studies showed that heterologous PrP-sen can bind to PrP-res with little conversion to the protease-resistant state and, in doing son, can interfere with the conversion of homologous PrP-sen. The interference occurred with molar ratios of homologous to heterologous PrP-sen molecules as low as 1:1. The interference was due primarily to the inhibition of conversion, but not the binding, of the homologous PrP-sen to Prp-res. The results provide evidence that the sequence specificity of PrP-res formation in this model is determined more by the conversion to protease resistance than by the initial binding step. These findings also imply that after the initial binding, further intermolecular interactions between PrP-sen and Prp-res are required to complete the process of conversion to the protease-resistant state.

In their report 'Porphyrin and phthalocyanine antiscrapie compounds' (25 Feb., p. 1503), Priola et al. present data showing that pthalocyanine tetrasulfonate (PcTS) and related compounds prolong scrapie incubation. They suggest [...]

The transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases for which no effective treatments are available. The likelihood that a bovine form of TSE has crossed species barriers and infected humans underscores the urgent need to identify anti-TSE drugs. Certain cyclic tetrapyrroles (porphyrins and phthalocyanines) have recently been shown to inhibit the in vitro formation of PrP-res, a protease-resistant protein critical for TSE pathogenesis. We now report that treatment of TSE-infected animals with three such compounds increased survival time from 50 to 300%. The significant inhibition of TSE disease by structurally dissimilar tetrapyrroles identifies these compounds as anti-TSE drugs., The TSEs are a group of rare, fatal neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease in deer and elk, and Creutzfeldt-Jakob [...]

The causative agent of the transmissible spongiform encephalopathies (TSE) or prion diseases, which include sheep scrapie, mad cow disease, and human variant Creutzfeldt-Jakob disease (vCJD), is still hotly debated. The [...]