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Biochemistry Friday Seminars - Using yeast to model human diseases: parasites to paralysis

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The unity of molecular and cell biology across the Eukaryotes makes yeasts favourable organisms with which to model both infectious and systemic diseases of humans.

In order to model infectious diseases, we have set up systems in which the infectious agent and the human host are modelled either within the same or separate yeast cells. For instance, many tropical diseases are caused by eukaryotic pathogens, including protozoa and nematode worms, with a very similar biochemistry to humans. This makes it difficult to identify agents that will kill the parasite but not the patient. The search for such drugs is also hampered by the fact that many of these parasites are difficult or impossible to culture in the laboratory. This is where yeast comes in. We have developed a robust, fully automated method to screen for potential anti-parasitic drugs. This system uses separate yeast strains whose growth is dependent on the expression of coding sequences specifying target enzymes from either the parasite or the human host. The yeast system thus permits multiple parasite targets to be screened in parallel and is also able to exclude compounds that do not discriminate between host and parasite enzymes.

We have also used yeast to model the interactions between pathogenic bacteria and their plant and animal hosts; in this case both pathogen and host are modelled by a single yeast construct. We have engineered yeast to inducibly synthesise unusual nucleotides that are involved bacterial pathogenesis. Interactions between these bacterial signalling molecules and the yeast cell can result in growth inhibition or death. We find that cdiGMP functions through a mechanism that must be compensated by ribonucleotide reductase activity or by functionally competent mitochondria. Synthesis of the human Mesh1 protein in yeast indicates that it may be required to protect human cells from the damaging effects of ppGpp during bacterial infection.

The forgoing experiments generated data on yeast purine nucleotide metabolism that could not be accurately predicted by existing models of yeast metabolism. Investigation of this deficiency led us to increase the representation of iron metabolism in the model and to discover that yeast has potential for modelling the cellular processes in involved in the onset and early progression of Parkinson’s disease. I shall discuss other examples of using yeast to model neurodegenerative diseases, including Friedreich’s Ataxia and motor neurone disease.

This talk is part of the Biochemistry Friday Seminars series.

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