Abstract

Studies using yeast models of Huntington's disease (HD) have provided insight into mechanisms underlying mutant huntingtin (htt) toxicity and have also identified several promising therapeutic targets for this disorder. Of particular note, we identified the candidate drug target kynurenine 3-monooxygenase (KMO) in a yeast genetic screen, which holds great promise in HD therapeutics. Complementing this loss of function screen, we have recently identified several mammalian cDNAs that suppress growth impairment in HD yeast. It is now critical to validate and characterise promising candidates from this screen in more physiologically relevant models of HD. The present study exploits a widely used and robust Drosophila model of HD to test rescue of three cDNA suppressors by several metrics, including neurodegeneration, longevity, locomotor activity and circadian rhythms. In our experiments, we are directing mutant htt exon 1 93Q transgene expression both temporally and spatially via three promoters: (1) elav—which directs expression in most neurons and (2) tim and pdf—which are expressed in all circadian clock neurons or a subset of them. We have generated multiple transgenic fly lines for three mammalian cDNAs that are in the process of being tested for rescue of disease relevant phenotypes. Interestingly, the work thus far has shown that all suppressor cDNAs tested rescue a subset of metrics to varying degrees. Importantly, this work suggests that compound treatments which mimic overexpression of these cDNAs may have therapeutic value in HD. In addition, this work strongly supports the rationale of identifying genes that modulate mutant htt toxicity in yeast.