Exploiting yeast genetics to inform therapeutic strategies for Huntington's disease.
Huntington's disease (HD) is a devastating neurodegenerative disorder that is inherited in an autosomal dominant fashion and is caused by a polyglutamine expansion in the protein huntingtin (htt). In recent years, modeling of various aspects of HD in the yeast Saccharomyces cerevisiae has provided insight into the conserved mechanisms of mutant htt toxicity in eukaryotic cells. The high degree of conservation of cellular and molecular processes between yeast and mammalian cells have made it a valuable system for studying basic mechanisms underlying human disease. Yeast models of HD recapitulate conserved disease-relevant phenotypes and can be used for drug discovery efforts as well as to gain mechanistic and genetic insights into candidate drugs. Here we provide a detailed overview of yeast models of mutant htt misfolding and toxicity and the molecular and phenotypic characterization of these models. We also review how these models identified novel therapeutic targets and compounds for HD and discuss the benefits and limitations of this model genetic system. Finally, we discuss how yeast may be used to provide further insight into the molecular and cellular mechanisms underlying HD and treatment strategies for this devastating disorder.
Giorgini
Flaviano
F
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
Muchowski
Paul J
PJ
D004353:Drug Evaluation, Preclinical / Q000379:methods; D023281:Genomics / Q000379:methods; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D010641:Phenotype; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins