Like the svelte catwalk models that dominate the fashion world, on first appearance the unicellular budding yeast Saccharomyces cerevisiae bears little resemblance to the average human being. However, just as a fashion model is employed by designers to represent the human form, so yeast is used by scientists as a model organism for investigating biological processes relevant to man. In the 6 November issue of Proceedings of the National Academy of Sciences, Robert Hughes et al. show that it might now be possible to use yeast as an in vivo system to screen for compounds to treat neurodegenerative disorders, such as Huntington's disease and the spinocerebellar ataxias. These devastating hereditary illnesses are characterized by their common cause: an expanded polyglutamine repeat in specific disease-associated proteins.

Although yeast is a unicellular organism, it is thought that ∼30–40% of its genes might have mammalian homologues. Despite its lack of a nervous system, this homology indicates that yeast could be used to analyse the cellular processes that underlie human neurodegenerative disorders.

Recent research has indicated that the pathology of polyglutamine diseases might be related to an interaction of expanded polyglutamine with constituents of cellular transcription complexes. In this study, DNA microarrays were used to analyse the effect of polyglutamine on the gene-expression profiles of yeast cells transformed with constructs that contained part of the human huntingtin gene, incorporating either 23 (nonexpanded) or 75 (expanded) glutamine-encoding CAG repeats, both with and without a nuclear localization signal (NLS).

It was found that some genes, such as those encoding chaperones and other molecules involved in protein folding, were induced by both nuclear and cytoplasmic expanded polyglutamine, whereas repression of various other genes was most pronounced in cells expressing nuclear expanded polyglutamine. Intriguingly, the pattern of gene repression in the strain expressing nuclear expanded polyglutamine (NLS-75Q) was similar to several yeast strains deficient in components of the SAGA (Spt/Ada/Gcn5 acetyltransferase) transcription complex, which is involved in histone acetylation. Modulation of histone acetylation regulates the transcription of some genes, with acetylation activating transcription and deacetylation repressing or silencing gene expression.

To investigate the role of histone acetylation in the transcription defect mediated by nuclear expanded polyglutamine, the repression of PHO84, one of the affected genes, was monitored in the presence of the histone deacetylase inhibitor, trichostatin A (TSA). Sure enough, cells expressing NLS–75Q that were treated with TSA showed significantly increased expression of PHO84, indicating that the repression of transcription caused by nuclear expanded polyglutamine might involve interference with histone acetylation.

The conservation of the transcription machinery from yeast to humans indicates that histone deacetylase inhibitors might be useful for treating polyglutamine disorders in man. This study, along with the one highlighted below from the same lab, emphasizes the potential of yeast as a versatile screening tool for identifying candidate drugs.