The pathways to prion formation in the response to oxidative stress

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Prions are protein-only infectious agents associated with a group of transmissible neurodegenerative diseases typified by human Creutzfeldt Jakob Disease (CJD). Although CJD is a rare disease, it shares many pathological features with other more common, non-infectious diseases of the brain such as Alzheimer's disease. In spite of its infectious nature, the majority of cases of human CJD appear spontaneously, without any evidence of infection by the associated infectious entity, the prion. However, the molecular basis of how prions form spontaneously into infectious structures is poorly understood at present. Prions are remarkable infectious agents because they consist only of a single protein that is a structurally altered form of a protein normally found in the brain. Yet we know very little about how prions form spontaneously to cause sporadic CJD or for that matter what will trigger their formation. To help us address these questions we are proposing to study prions that are found in Baker's yeast (Saccharomyces cerevisiae). Prions were first described in this fungus some 30 years ago and the subsequent studies on yeast prions have revealed many fascinating new aspects of prion biology. In our recent research we have discovered that certain dangerous forms of oxygen known as reactive oxygen species (or ROS) can trigger the spontaneous formation of prions in yeast, because cells lacking the defence system preventing such oxidative damage, form prions spontaneously at a remarkably high frequency. We are now interested in determining how oxidative damage to a normally soluble protein triggers its conversion into the prion form. Importantly, our novel genetic approaches will be relevant to understanding the underlying mechanisms of prion formation in man and animals. In the long term, findings from these studies may therefore reveal candidates for potential therapeutic intervention in the treatment/management of prion diseases.