Genetics of sleep regulation and function: the AKR genes in Drosophila

Sleep needs no introduction. We humans spend about one third of our lifetime asleep but no one knows why. Astonishingly, sleep still remains one of the most puzzling problems of biology despite decades of research. While something is known about the mechanisms regulating occurrence of sleep, nothing is known about its functions: why sleep deprivation has detrimental effects on the body and the brain? Why is sleep restorative? What happens in our cells as we sleep? Why sleep architecture and sleep needs are so different amongst different individuals and why do they change so much as we age? The answer to those questions is likely to be in our genes: gene activity may explain what happens at the cellular level when we sleep and similarly when we deprive ourselves from resting. Our laboratory has chosen to explore genetics of sleep using the fruit fly Drosophila melanogaster as animal model. Drosophila is arguably the most powerful and most commonly used genetic animal model. Importantly, not only do flies sleep but in fact their sleep vastly reminds of human sleep: flies sleep at night like us; their sleep is restorative; sleep deprivation leads to detrimental performances and eventually to death; their sleep is homeostatically regulated (i.e. a sleep deprived fly will have stronger sleep pressure) and, importantly, their sleep is modulated pharmacologically by the same compounds that are known to affect human sleep, such as caffeine or modafinil, suggesting an evolutionary conservation for functions and genetics of sleep. Understanding the basic biology of sleep is not just a fascinating scientific puzzle: it is also key to understand and mitigate the effects of social sleep deprivation, insomnia or sleep disorders - a very pressing need for today's society.

Recently we have identified a new gene called allnighter. Flies that are mutant in the allnighter gene sleep considerably less than normal (50% less). We aim to elucidate the biology behind this observation. Some of the questions we are addressing are: how does allnighter work to regulate sleep duration? How do allnighter mutant flies cope with sleep deprivation? Is allnighter acting in the brain of the fly and , if yes, in what neurons exactly? What is the general mechanism of action of allnighter and is there a functional allnighter equivalent in other species? Finally, the allnighter gene shares similarities with other known genes affecting sleep in flies and rodents: we aim at exploring those connections too, arguing this will provide a new perspective on the mystery of sleep function.

Sleep is an evolutionary conserved animal need. All organisms that have been tested so far have shown to possess and to require the basic characteristics of sleep: that is circadian and homeostatic regulation, restorative effects of sleep, detrimental effects of sleep deprivation. Our laboratory studies genetics of sleep in Drosophila melanogaster, with the aim of uncovering genes and mechanisms regulating sleep functions and regulation.
Recently, we have identified a new mutation, allnighter, that leads to an abnormally short sleeping phenotype in Drosophila. The allnighter gene is predicted to encode for at least two proteins belonging to the family of Drosophila Aldo Keto Reductase genes, an evolutionary conserved family of NAD(P)(H) oxidoreductases that reduce aldehydes and ketones to alcohols. Interestingly, Drosophila melanogaster is predicted to have 12 AKR genes, of which two appear to play a crucial role in regulating sleep: allnighter and Hyperkinetic. Hyperkinetic, together with Shaker and Sleepless, is believed to modulate sleep length through regulation of cellular K+ currents.
This work has two main objectives: 1) characterise how allnighter regulates sleep; 2) investigate what role the AKR domains of allnighter and Hyperkinetic play in their function and whether any other Drosophila AKR protein is involved in sleep regulation.

Other than the impact on academia discussed above, we will work to ensure our research will also have proper economic and societal impacts. In this section we discuss who might benefit from this research and how. In the next section we will highlight what will be done to ensure that potential beneficiaries have the opportunity to engage with this research.

Societal impact.
Sleep is not merely a fascinating biological problem, but also a topic of medical and social relevance. Sleep deprivation has become an endemic condition in our modern 24/7 society, where artificial lights, television sets and alarm clocks dictate our activity and rest. According to the latest "Great British Sleep Survey" published in 2011 and directed by Prof. Cloin Espie, 51% of Britons will lament sleep problems of sort, mainly linked to insomnia. It is estimated that about one third of the population in western countries is chronically sleep deprived and that one quarter is regularly working night shifts, thus impairing not only their sleep quality but also their circadian rhythms. How can our study help solve this issue? Firstly, by raising awareness. Scientific studies on sleep and sleep deprivation are usually very well received by the public and highly covered on national and international press ("Google News" reports 132000 news entries containing the keyword sleep, only in 2013). Any scientific study that addresses the consequences of sleep deprivation will help the public understand the importance of a good night's sleep on our health. In our experience, the mere fact that we study sleep using fruitflies as animal model will increase even further the public interest for our research: the very concept that flies can sleep like humans, be sleep deprived and suffer of learning impairment is very fascinating for the public (and in fact for scientists, too!). The second potential effect of our research has to do with the science itself: discovering new genes regulating sleep duration or sleep function means providing the pharmaceutical industry of a new potential target for sleep-related drugs. This is particularly relevant in our case, because the AKR proteins that we are studying are well known drug targets for a number of conditions (e.g. steroid production, immunoresponse, cancer).

Economic impact.
As for the societal impact, also the economic impact has a short term and a long term component. The long term component is linked to the general consequences of improving sleep conditions in people's life: the estimated economic cost of sleep deprivation in the USA alone is $20-30 billions [Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. ISBN 030965727X]; 20% of all road accidents are associated with driver sleepiness and sleep deprivation can affect virtually any other risky human activity, from operating machineries to performing surgery. Therefore, the economic impact of ameliorating sleep conditions is astonishingly high.
The short term component relates to translating the work from academia to industry: as mentioned above, any novel sleep-regulating gene is a potential target for a sleeping pill of the future. Importantly, also the technological aspects of our work are of interest to industry: some of the machines and techniques we have built are now commercially available, produced and sold by a London based startup for which I have acted as mentor and advisor for the past year (more about this in "Pathways to Impact".)