Abstract
Deficit in locomotion (motor) ability and disturbance of the circadian behavior and sleep-wake pattern characterize Huntington's disease (HD). Here, we examined the disturbance of circadian timing with the progression of HD pathogenesis, and tested the efficacy of melatonin and curcumin in preventing the motor deficit and disturbed eclosion behavior in the Drosophila model of HD. To examine circadian timing, we assayed mRNA expression of genes of the transcriptional feedback (TF) loop that generates the near 24-h rhythmicity. We performed qPCR of the Period, Timeless, Clock, Cycle, Clockwork, and Cryptochrome genes in transgenic fly heads from elav-Gal4 (pan neuronal) and PDF-Gal4 (PDF-specific neurons) driver lines through the progression of HD disease post-eclosion, from day 1 to its terminal stage on day 13. Cycle was arrhythmic from day 1, but Period and Timeless became arrhythmic on day 13 of the HD pathogenesis in elav, but not PDF, neurons. Twenty-four-hour mRNA rhythms showed alteration in the waveform properties (mesor and amplitude, not acrophase), but not in the persistence, in both elav-Gal4 and PDF-Gal4 HD flies; however, disturbance of the clock gene rhythm was delayed in PDF-Gal4 flies. To assess the preventive effects on HD pathogenesis, flies of both driver lines were provided with melatonin (50, 100, or 150 μg) or curcumin (10 μM) in the diet commencing from the larval stage. Both melatonin (100 μg) and curcumin reestablished the 24-h pattern in mRNA expression of Period and Timeless to normal (control) levels, and significantly improved both locomotion ability and eclosion behavior of HD flies. We suggest that the disturbance of circadian timekeeping progressively accelerated HD pathogenesis, possibly via modulation of the transcriptional state that resulted in the modification of the Huntington gene. These findings suggest melatonin and curcumin might be potential therapeutic agents for the treatment of HD in humans, although this needs specific investigation.
