Background Circadian rhythms are daily rhythms that control every aspect of our behaviour and physiology in a 24 h fashion. They are common to nearly all living organisms from cyanobacteria to plants and from flies to humans. The underlying molecular mechanisms that control circadian rhythms are well understood and flies are an excellent model to study them as their clock is very similar to ours. Additionally we have high-throughput techniques to analyse the fly’s locomotor activity rhythms, which are equivalent to our sleep/wake cycles. Circadian rhythms are also very sensitive physiological markers of wellbeing and can be easily disturbed by life style changes such as inter continental travel or shift work. Circadian problems can also be the direct or indirect result of brain pathologies as in the case with Huntington’s disease (HD).
Aims We are characterising a new fly model of HD that is inducible, tuneable and cell type specific. Our aim is to understand early cellular and physiological processes that lead to neuronal dysfunction by using the circadian clock as a readout. Our work may shed light on several under explored areas. For instance: Is HD pathology directly caused by progressive accumulation of mutated huntingtin (HTT) protein over time or by the ageing cell not being able to cope with the mutant protein? Can we reverse HD pathology by turning off the mutated gene? If so, when is the critical point of no return?
Methods Using the molecular toolkit available for flies, we can over-express mutant human HTT protein in the brain targeting the clock neurons. We can then analyse rhythms of locomotor activity, looking for anomalies in period, phase or amount of locomotion. Turning the mutant HTT gene on or off throughout the life span of the fly we can probe the effects of ageing on rhythmic phenotypes.
Results Here we show that over expression of mutant human HTT in clock neurons causes arrhythmic behaviour in flies and that this effect is modulated by ageing.
Conclusions Using circadian rhythms as a tool and fruit flies as a model we have a powerful experimental system to study the pathology caused by the mutated HD protein. In the future, we will focus on the cellular mechanisms leading to neuronal dysfunction/ neurodegeneration in HD and define the critical point in the progression of the disease before which intervention should be made.
- Huntington’s disease
- circadian rhythms
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