Hunting for the function of Huntingtin.

the gene responsible for HD (HTT) was cloned, representing a major breakthrough in the field. HTT encodes a large protein that was named Huntingtin (Htt). The N-terminal portion of Htt contains a stretch of glutamines (the polyQ tract) and HD patients harbor pathogenic polyQ expansions (Andrew et al., 1993; Bates et al., 1998). Although the polyQ length can vary, all healthy individuals have fewer than 37 glutamines and those with greater than 40 are certain to develop HD (Rubinsztein et al., 1996). Moreover, the length of the polyQ expansion correlates inversely with the age of disease onset (Andrew et al., 1993). Experiments in cell culture and animal models have clearly established that an expanded polyQ tract is toxic (Cattaneo et al., 2001). However, little is known about the normal cellular function of Htt and how this might be disrupted in HD. In vitro studies identified a wide range of Htt-interacting proteins and suggest that wild-type Htt may be involved in such diverse biological processes as protein trafficking, vesicle transport, anchoring to the cytoskeleton, clathrin-mediated endo-cytosis, postsynaptic signaling, transcrip-tional regulation and anti-apoptotic functions (Gil and Rego, 2008; Imarisio et al., 2008). As a model organism, the fruit fly Drosophila melanogaster has many experimental advantages, including a short life span; large and rapid reproductive capacity; a vast array of available genetic information from its fully sequenced genome; and an extensive collection of powerful genetic tools. Importantly, Drosophila shares many essential features with higher-order organisms. Approximately 75% of human disease genes have at least one Drosophila homolog. Compared with other simple systems, Drosophila is particularly suitable for studying neurodegenerative disease because of its complex nervous system and behaviors (Bilen and Bonini, 2005). Jackson et al. first showed that the human Htt-Q75 and-Q120 transgenes induce degeneration of fly pho-toreceptor neurons (Jackson et al., 1998). Li et al. later identified a Drosophila homolog of HTT (htt, hereafter referred to as dhtt) (Li et al., 1999). However, the normal function of Drosophila Htt (dHtt) remains elusive. A new study by Zhang et al. in the current issue of DMM explores the function of dHtt in a unique model of HD (Zhang et al., 2009). First, the authors used reverse transcription -PCR and in situ hybridization to demonstrate that dhtt is expressed ubiquitously during all stages of fly development (see fig. 1 in Zhang et al.). Also, with an anti-dHtt antibody, they confirmed that, like its mammalian …