Modeling Huntington Disease in Yeast and Invertebrates

Huntington disease (HD) is a fatal, late-onset neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the huntingtin gene (HTT), which encodes a polyglutamine (polyQ) tract with a high propensity to misfold and aggregate. Mutant HTT is believed to act predominantly via a gain-of-toxic-function mechanism, leading to a myriad of downstream dysfunctions at the cellular level, culminating with generation of disease symptoms. The gain-of-function nature of this mutation has permitted the development of several transgenic models of HD that express all or a portion of human HTT containing the polyQ stretch, including yeast, nematode, fruit fly, and mouse. While murine models of HD have become the mammalian system of choice—and the gold standard for preclinical testing of drug-like compounds—yeast and invertebrate models have been used extensively and have made major contributions to both the understanding of the pathogenesis of HD and the identification of candidate therapeutic targets and compounds for this disorder. Here we provide an overview of these models and discuss how they have contributed to our understanding of HD.