The role of oxidative stress in the patho-aetiology of prion disorders using infected cell culture and animal models

点击翻译按钮获取中文摘要

The transmissible spongiform encephalopathies (TSE; also known as prion diseases) are a biologically unique and fascinating group of invariably fatal diseases which primarily affect the brains of both humans and animals. In humans, sporadic Creutzfeldt-Jakob disease (CJD) is the most common form, while in animals it is the recent epidemic of bovine spongiform encephalopathy (mad cow disease), and its probable transmission to humans as new variant CJD, which has drawn so much attention to this group of disorders. The preponderance of scientific evidence now supports the belief that infectivity in TSEs relates predominantly (probably exclusively) to a protein (called the prion protein; PrP) which is normally found on the cell surface of a number of types of brain cells, including neurons. Transmissibility, and hence infectivity, is more correctly associated with a malfolded version of PrP into an abnormal shape which gives the mutant protein significantly different biological and biochemical properties, including relative resistance to breakdown by enzymes that metabolise proteins (proteases) and enhanced tendency to aggregate. However, the precise steps involved in this transformation to the abnormal infectious form of PrP are not known. Similarly, our understanding of how different folding and accumulation of this protein brings about disease is not clear. Nevertheless, as with other neurological diseases (eg Alzheimer's disease) which are a consequence of unexplained spontaneous premature degeneration of parts of the brain (neurodegenerative diseases), oxidative stress is increasingly believed to play a role. Oxidative stress is a generic term used to describe the enhanced production within a cell of small, very harmful, oxygen containing molecules which under normal circumstances can be successfully detoxified. This project involves a detailed study of the role of oxidative stress in the causation of prion diseases using both mouse and cell culture models.