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A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease.


ABSTRACT: Huntington disease is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the protein huntingtin (Htt), which leads to its aggregation in nuclear and cytoplasmic inclusion bodies. We recently identified 52 loss-of-function mutations in yeast genes that enhance the toxicity of a mutant Htt fragment. 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 species. 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.

SUBMITTER: Giorgini F 

PROVIDER: S-EPMC1449881 | biostudies-literature | 2005 May

REPOSITORIES: biostudies-literature

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A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease.

Giorgini Flaviano F   Guidetti Paolo P   Nguyen QuangVu Q   Bennett Simone C SC   Muchowski Paul J PJ  

Nature genetics 20050403 5


Huntington disease is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the protein huntingtin (Htt), which leads to its aggregation in nuclear and cytoplasmic inclusion bodies. We recently identified 52 loss-of-function mutations in yeast genes that enhance the toxicity of a mutant Htt fragment. 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  ...[more]

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