Huntington disease is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the protein huntingtin (Htt)1, which leads to its aggregation in nuclear and cytoplasmic inclusion bodies2. We recently identified 52 loss-of-function mutations in yeast genes that enhance the toxicity of a mutant Htt fragment3. Here we report the results from a genome-wide loss-of-function suppressor screen in which we identified 28 gene deletions that suppress toxicity of a mutant Htt fragment. The suppressors are known or predicted to have roles in vesicle transport, vacuolar degradation, transcription and prion-like aggregation. Among the most potent suppressors was Bna4 (kynurenine 3-monooxygenase), an enzyme in the kynurenine pathway of tryptophan degradation that has been linked directly to the pathophysiology of Huntington disease in humans by a mechanism that may involve reactive oxygen species4. This finding is suggestive of a conserved mechanism of polyglutamine toxicity from yeast to humans and identifies new candidate therapeutic targets for the treatment of Huntington disease.
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We thank M. Sherman for the pYES2-Htt25Q and pYES2-Htt103Q plasmids, S. Lindquist for the RNQ antibody and the pdr1Δpdr3Δ drug testing strain, W. Frostl for Ro 61-8048, R. Schwarcz for discussions about our data and advice regarding this project and K. Neireiter for his illustration. P.J.M. is supported by the US National Institute of Neurological Disease and Stroke, by a US National Institutes of Health construction award, by the Alzheimer's Disease Research Center at the University of Washington and by the Hereditary Disease Foundation under the auspices of the Cure Huntington's Disease Initiative. F.G. is supported by a postdoctoral fellowship from the HighQ foundation.
The authors declare no competing financial interests.
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Giorgini, F., Guidetti, P., Nguyen, Q. et al. A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nat Genet 37, 526–531 (2005) doi:10.1038/ng1542
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