Characterisation of candidate therapeutic targets for Huntington disease

Huntington disease is a fatal hereditary disorder that is characterised by the formation of lesions in the brain. It is a late onset disease in which patients exhibit involuntary movements, rigidity, and dementia. Though a great amount of work has been focused on this disease in recent years, no effective therapy is yet available for Huntington disease.
Genetic analysis in bakers yeast has been used extensively as a fast and easy approach to study genetics and cellular processes. We have previously used a yeast model of Huntington disease to identify a candidate therapeutic target for this disease, which has recently been validated in preclinical trials in a mouse model of Huntington disease.
Here, we propose to validate additional candidate therapeutic targets identified in yeast in mammalian cells. In addition, we will use yeast to characterise the genetic interactions among the identified modifiers. Ultimately, we feel this work will elucidate the molecular mechanisms of pathogenesis in Huntington disease as well as inform novel therapeutic approaches for this disorder.

Huntington disease is a fatal neurodegenerative disorder inherited in an autosomal dominant manner. Though a great amount of work has been focused on this disease in recent years, no effective therapy is yet available. We have identified many candidate therapeutic targets for this disorder via a genomic screen in yeast. Recently, we have validated one of these targets in mammalian cells and in a mouse model of Huntington disease, indicating that this is a valid approach for identifying novel drug targets for this disorder. The major goals of the proposed studies are to use molecular genetic approaches to validate the additional candidate therapeutic targets and to thereby dissect the pathogenic pathways causing neurodegeneration in Huntington disease. Here we propose to identify additional genes that modulate toxicity in a yeast model of Huntington disease by testing candidate genes identified in gene expression profiling experiments. In addition, we will dissect the genetic interactions among these genes and other genetic modifiers of toxicity identified in a yeast model of Huntington disease. Finally, we will validate the modifiers of toxicity in mammalian cell models of Huntington disease.