Molecular and phenotypic analysis of human prion strains

Prions, the infectious agents causing BSE in cows and variant CJD in humans are unique in medical research. Unlike all other infectious agents (bacteria and viruses) the infectious particle does not contain genetic information (genes) but instead consists of a protein (called PrPSc). Although prions do not carry genetic material they come in several different forms, called prion strains that cause different forms of the disease. Our research aims to understand the fundamental biology of what makes prion strains different from one another and why some are able to cross from animals to humans to cause disease. Understanding these differences is vital to providing early diagnosis and to developing effective cures that halt the spread of prion infection and prevent fatal brain damage.||Our research focuses on isolating infectious prion particles from diseased tissue and using sophisticated equipment to study their chemical makeup. Through these studies we aim to provide a detailed description of the protein (PrPSc) associated with each prion strain and pinpoint exactly what differences are responsible for a particular form of disease. For some studies we use a prion strain (RML prions) that can be detected in isolated cells allowing us to make much faster progress than has been previously possible. In other studies we use genetically altered mice (transgenic mice) to understand which animal prion strains may pose a risk to humans and to see what these diseases may look like should people become infected. These studies have confirmed that variant CJD is caused by the same prion strain that causes BSE in cows and have established that a persons genetic makeup may influence the type of prion disease they will develop if infected with BSE prions.||Because of the very long time periods possible between infection and the appearance of symptoms the number of people with BSE infection is unknown. This has raised fears that infected people who have no signs of the disease might pass it on to others by surgery, blood transfusion and other medical routes. We have pioneered laboratory tests to rapidly detect variant CJD and other forms of disease caused by BSE infection should they occur. Our findings have been used throughout the world to help accurately diagnose human prion diseases and have assisted the World Health Organisation to develop measures to limit the spread of these diseases from one person to another by medical procedures.

Prion diseases are fatal neurodegenerative disorders that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI), kuru and most recently variant CJD (vCJD) in humans. Their central feature is the conversion of a normal host protein, the cellular prion protein (PrPC), to an abnormal isoform, designated PrPSc. This transition appears to involve only conformational change rather than covalent modification and confers PrPSc with resistance to proteolytic degradation and detergent insolubility. The marked clinical heterogeneity observed in human prion diseases has yet to be explained. However, it has been clear for many years that distinct isolates, or strains, of prions can be propagated in the same host and these are biologically recognised by distinctive clinical and pathological features. It is therefore likely that a proportion of clinicopathological heterogeneity seen human prion diseases relate to the propagation of distinct human prion strains. How this strain diversity is encoded by an apparently protein-only agent remains one of the most interesting and challenging questions in biology. Although distinct mammalian prion strains are associated with different prion protein conformations and glycoform assembly states their precise composition and the molecular determinants of strain remain unknown. Our integrated series of research projects aim to define the molecular composition and ultra-structure of infectious prions and elucidate the molecular basis of prion strain diversity. Knowledge generated by this research is expected to have direct translational benefit by facilitating improved methods of diagnosis and therapeutic treatments for human prion disease.