Modelling neuropsychiatric disorders in Drosophila melanogaster

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandlingForskning

Gianna Wen Maurer

Neuropsychiatric disorders, characterised by deficits in cognitive processes and perceptions, present a global health burden. Current medications for psychiatric disorders are limited, with barely any new medications reaching the market in the past 20 years. To develop new treatment strategies, the mechanisms underlying neuropsychiatric disease need to be better understood. Recent genome-wide association studies (GWAS) have identified rare copy-number variants (CNVs) that confer high disease risk. The CNVs span intervals of various sizes containing multiple genes and investigating these CNVs, offers a route to characterising genetic mechanisms underlying the development of neuropsychiatric disorders. Although each CNV is highly associated with disease risk, the contribution of individual genes within each interval to disease development, is generally unclear. Using the fruit fly Drosophila melanogaster as a model system, this PhD project aimed to identify and characterise the biological impact of individual CNV-linked genes from two CNVs associated with neuropsychiatric disease, the 1q21.1 and 22q11.2 deletions. The Drosophila system is a powerful tool for the study of genetics and behaviour, displaying conserved complex behaviours such as learning and sleep. As disruptions of these basic behaviours are thought to cause many of the symptoms of neuropsychiatric disease, investigating the role of individual CNV-linked genes on some of these behaviours in Drosophila may provide insight into underlying disease mechanisms. This thesis encompasses two manuscripts. In Manuscript I, we show a requirement for the gene alicorn (alc), the Drosophila orthologue of the human 1q21.1-linked gene PRKAB2, in several behaviours, including sleep and learning. Alc is a component of the conserved AMPK complex, known as a key metabolic regulator in both humans and Drosophila. In Manuscript II, we describe an unbiased screening approach used to identify a candidate gene from the 22q11.2 CNV. Using an in-vivo RNAi sleep screen, we identified the gene CG3711, the Drosophila orthologue of human LZTR1, as a modulator of sleep. We chose to name the previously uncharacterised gene “night owl” (nowl), as knockdown of the gene in the nervous system resulted in severe sleep loss and fragmentation, particularly during the night. We found that nowl functions in GABA-responsive neurons, and is required for sleep maintenance, possibly through interaction with the gene Cul3. This thesis work has identified and characterised two Drosophila orthologues of human genes linked to CNVs associated with psychiatric disorders, describing novel roles for both genes in sleep maintenance. Given the evolutionary conservation of many behaviours and systems between the fly and the human, especially of the genes identified here, we believe that these findings may contribute to the understanding of the mechanisms underlying neuropsychiatric disorders. In particular, we propose that disturbances in these genes might contribute to the behavioural deficits experienced by individuals affected by the 1q21.1 and 22q11.2 CNV deletions.
OriginalsprogEngelsk
ForlagDepartment of Biology, Faculty of Science, University of Copenhagen
StatusUdgivet - 2019

ID: 218722185