Effects of temporally controlled huntingtin expression and autophagy upregulation in drosophila melanogaster

Abstract

Previous studies in the laboratory have shown that expression of pathogenic human Huntingtin (HTT-Q128) in circadian pacemaker neurons (ventro lateral neurons, LNv) of Drosophila, leads to immediate behavioural arrhythmicity in constant darkness and loss of neuropeptide Pigment Dispersing Factor (PDF) specifically from a subset of LNv - the small LNv (sLNv), while the large LNv (lLNv) are intact. In the present study, we have attempted to examine effects of temporally restricting HTT expression in LNv on neuronal function and behaviour using an inducible Gene Switch system that enables HTT induction only in the presence of a progesterone analogue RU. We used this system to ask whether larval versus adult specific HTT induction alters the selective vulnerability of sLNv and circadian behavioural dysfunction (arrhythmic locomotor activity) under constant darkness. It was seen that either adult-restricted or larval-restricted HTT induction were each sufficient to render flies arrhythmic, albeit to different magnitudes. Moreover, the onset of arrhythmicity was delayed compared to flies expressing HTT throughout. Both these treatments were also sufficient to cause loss of PDF in sLNv; but at a slower rate compared to flies expressing HTT throughout. Therefore, the selective susceptibility of sLNv does not seem to depend on the life-stage at which HTT is expressed, but the rate of loss seems to be affected by the duration of HTT expression.