In prion and Alzheimer's diseases, the roles played by amyloid versus nonamyloid 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.
The transmissible spongiform encephalopathies (TSEs) are a class of neurodegenerative diseases that are characterized by proteinaceous deposits in the brain. The deposits consist largely of an abnormal form of prion protein which is highly aggregated and resistant to degradation by proteases. The function of prion protein (PrP) is unknown and its normal form (PrPC) is sensitive to protease digestion. Some of the TSEs include scrapie in sheep, mice, and hamsters, bovine spongiform encephalopahty, and Creutzfeldt-Jakob disease in humans. Animals with scrapie accumulate a disease-specific form of PrP designated PrPSC. The identity of the infectious agent of the TSEs is unclear. No conventional agent or disease-specific nucleic acid has been found and treatments that destroy most normal viruses have no effect. Based on that information the infectious particle has been surmized to consist solely of protein.The "protein only" theory has been strengthened by the discovery of PrP and that preparations of PrPSc are greatly enriched for infectivity. Previously, the simplest system producing protease-resistant PrP was cell culture. Here is described a system that produces protease-resistant PrP in vitro. This system was used to study the mechanism of the conversion of PrPC to the protease-resistant form. A threshold concentration of aggregates of PrP S c was required for conversion. Guanidine-HCI solubilized PrPSC had no converting activity. The need for aggregates and a threshold concentration favors a seeded polymerization mechanism of conversion. The system was also used to study species barriers and different strains of scrapie. Different combinations of mouse and hamster PrPs were used in conversion reactions. The in vitro conversion results correlated with infectivity data on transmission. Scrapie strains with different PrPSc N-terminal protease cleavage sites were used with this system. These different cleavage sites were passed to newly-resistant PrPC depending on which strain was in the reaction. This system provided evidence that a "protein only" theory is compatible with the properties of TSEs.Thesis Supervisor: Dr. Peter T. Lansbury, Jr. Title:Associate Professor of Chemistry Chapter 1 CJD is characterized by dementia, ataxia (a loss of muscle coordination), and the formation of small holes in the brain known as spongiform degeneration.This spongiform degeneration is the result of a loss of neurons. CJD is often accompanied by abnormal proteinaceous deposits known as amyloid plaques.The onset of CJD can be months to years after infection, but once the disease presents itself a gradual deterioration of mental capabilities ensues. The deterioration ends in death usually within a year of onset. Heparin sulfates have been shown to offer some protection to mice inoculated with scrapie,7 but as of now there is no way to stop the deterioration and the disease is always fatal.GSS is a familial version of CJD with different pathology. All GSS cases are accompanied by the formation of amyloid plaques 2 and it i...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.