A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease.
Nat Genet
; 37(5): 526-31, 2005 May.
Article
en En
| MEDLINE
| ID: mdl-15806102
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Saccharomyces cerevisiae
/
Enfermedad de Huntington
/
Oxigenasas de Función Mixta
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Nat Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2005
Tipo del documento:
Article
País de afiliación:
Estados Unidos