Functional and biochemical analysis of oligomeric intermediates of yeast prions formed in vivo

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For over a century there has been a near universal acceptance of Mendel's Laws of Inheritance to explain the faithful transmission of genetic information from one generation to the next. A nucleic acid-based hereditary unit, the gene, carries this information and the characteristics of an organism are defined by its set of genes. Over the last century a number of exceptions to Mendel's Laws have been identified, but a new challenge to the dogma that all inheritance is nucleic acid based has recently arisen from the discovery of prions. Although prions have been intensively studied as the disease-causing agents associated with 'Mad Cow Disease' and the human equivalent, Creutzfeldt-Jakob Disease (CJD), there is now a considerable body of scientific evidence that prions might actually represent an entirely new form of heredity, based on a protein molecule rather than a nucleic acid. This evidence comes from the analysis of novel prion-based 'genetic' determinants in Baker's Yeast (Saccharomyces cerevisiae) one of which (the so-called [PSI+] element) is being studied in this project. Our aim is to fully understand how such a protein-based determinant is generated de novo and then replicated aand passed on to other yeast cells when they grow and divide. We know that this requires cells to produce prion seeds which can be passed on to other cells and it is our objective to define the molecular composition of these seeds. Uisng advanced genetic and biochemical methods we will study different yeast prions and look in particular at the type of physical changes they go through in taking up their prion form. One outcome of this research might be identifying steps in the prion cycle that can be targetted by new drugs to block the formation of prion seeds.