Neurodegenerative diseases, such as Alzheimer's and Huntington's, commonly involve the accumulation and aggregation of neurotoxic proteins that impair and ultimately destroy specific neurons. Identifying processes that can slow neurodegeneration, especially before irreversible cell death, is a major challenge for the development of effective therapeutics. Accumulating evidence suggests that disrupted clocks are associated with, and even potentially alter, neurodegeneration at this early stage. To address the mechanistic relationship between circadian clocks and neurodegenerative diseases, we are using Huntington's disease (HD) as a model. HD is caused by a triplet repeat expansion resulting in an expansion of a polyglutamine repeat in the Huntingtin protein (mHtt). Accumulation of mHtt results in degeneration of striatal as well as cortical neurons, resulting in the characteristic motor and cognitive symptoms, and ultimately death. Considerable evidence from human and animal studies indicates that mHtt impairs circadian rhythms often before characteristic motor symptoms are even evident. In fact, master circadian pacemaker neurons are lost in HD patients. Yet little is known about the molecular mechanisms by which mHtt impairs circadian rhythmicity. In addition, it is unknown if circadian clocks, in turn, can modulate HD pathogenesis. Tostudy the interplay between clocks and HD, the fruit fly Drosophila, a well-established model organism in the study of neurodegenerative disease and circadian clocks, has been employed. Both environmental and genetic perturbations of the circadian clock were shown to alter mHtt-mediated neurodegeneration, revealing that circadian clocks are not only a target of mHtt but may also be an important player in mediating mHtt-mediated pathogenesis. To identify potential genetic pathways that mediate the effect of the clock on mHtt, a novel behavioral platform has been developed for screening HD modifiers that would allow the identification of those genes that can modify pre-degenerative/functional and/or cell death effects of mHtt. As part of this screen, several novel pathways that mediate mHtt effects on behavior have been discovered. Here this successful screen will be expanded to discover novel pathways. In addition, the molecular mechanisms by which novel modifiers function will be explored in terms of mHtt inclusions, molecular clocks, and cell death. These deep conservation with vertebrate studies exploit the advantages of the Drosophila system including the models of circadian clocks and mechanisms of pathogenicity. HighmHtt throughput fly genetics will be applied to reveal the elusive molecular and cellular pathways that bi-directionally link mHtt to clock disruption, a relatively understudied area of HD pathology and thus one ripe for the discovery of novel mechanisms.