A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease.
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.
Giorgini
Flaviano
F
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
Guidetti
Paolo
P
Nguyen
QuangVu
Q
Bennett
Simone C
SC
Muchowski
Paul J
PJ
D001343:Autophagy / Q000502:physiology; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase; D017628:Microglia / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism
D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase