Clinical issue

Huntington’s disease (HD) is a degenerative brain disorder affecting approximately 30,000 people in the USA alone. It is characterized by involuntary movements (chorea), psychiatric symptoms such as irritability and delusions, and memory loss. These symptoms are progressive causing eventual incapacity and death.

HD is caused by an expansion of a CAG trinucleotide repeat in a single gene called huntingtin (HTT). Normal individuals have fewer than 34 CAG repeats, whereas HD patients have more than 35. The repeat length correlates inversely with the age of disease onset. Each CAG encodes a glutamine (Q) residue, so the protein product from HTT in HD has a longer glutamine tract, also known as a polyQ tract. Studies in different model systems, including yeast, fruit flies and mice, show that an expanded polyQ tract is toxic to cells. In addition to HD, a further eight neurodegenerative diseases are now known to be caused by the expansion of CAG repeats in eight other unrelated genes. Although Htt and other polyQ proteins are expressed widely, each polyQ disease selectively affects distinct, largely non-overlapping populations of neurons in the brain, suggesting that altering the normal function of the polyQ genes contributes to disease pathogenesis. However, the normal cellular function of Htt is largely unknown and the study of Htt is impeded by the absence of a tractable genetic model, since mice lacking Htt die during early embryogenesis.


In this study, the Drosophila HTT homolog (htt, hereafter referred to as dhtt) was removed from the fly genome and its effect on development and neuronal function was characterized. Like vertebrates, Drosophila melanogaster (i.e. the fruit fly) has a single Htt-like gene (dhtt) but, unlike vertebrates, flies lacking dhtt develop normally. The authors find that several cellular processes that are suspected to require the wild-type Htt protein, such as neuronal development, axonal vesicle transport and neuronal transmission, are not significantly affected by the loss of dhtt. Instead, dhtt-deficient flies display mild adult phenotypes, including reduced complexity of axonal termini in the adult brain, declining mobility with age, and a shortened life span. Furthermore, when an established fly HD model (transgenic flies expressing a mutated human Htt fragment with an expanded polyQ tract in the nervous system) was analyzed in the absence of endogenous dhtt, animals developed neurological symptoms (e.g. incoordination and shaking, and reduced activity and viability) much more quickly, suggesting a protective function of the wild-type dhtt gene.

Implications and future directions

This study demonstrates that the fruit fly Htt ortholog is required for maintenance of mobility and long-term survival of adult animals, and its activity affects the fine structure of axonal termini in the brain. This work also provides in vivo evidence that disruption of the normal function of the Htt gene enhances HD disease progression. Together with previous mammalian studies, these results imply that both the presence of mutant protein and the depletion of the normal protein contribute to HD pathology. However, this study suggests a therapeutic potential for partial depletion of the endogenous Htt protein, using RNA interference for example, since removing the fly dhtt gene has only mild effects. This fly model should lend itself to future understanding of the molecular events contributing to HD, such as the role of the wild-type Htt protein, and identify good target areas for therapeutic intervention.