Why did we fund this project?
This award aims to develop a Drosophila based platform to analyse genetic components of epilepsy replacing the use of some mice in this research area.
The underlying causes of epilepsy are not always clear, although some patients have a hereditary form of epilepsy. These often co-occur with sleep disorders or movement disorders such as ataxia. A large number of potential gene candidates for these hereditary conditions have been identified in genomic studies, and research is ongoing to confirm any causative genes. These studies typically use mice with transgenic models created to determine whether the mutations are linked to seizures. These models are often classified as severe under the UK’s Animals (Scientific Procedures) Act 1986 because of the level of suffering caused. Drosophila has the potential to be used as an alternative model system as approximately 70% of human genes are also conserved in the fly. Based on current thinking, Drosophila are not considered capable of suffering and therefore provide a replacement for the use of vertebrate animals used in research.
Dr Manolis Fanto aims to enable easier uptake of Drosophila in epilepsy research by developing automated, high-throughput methods to assess seizures. These will include assays to analyse both behaviour and neural activation in seizures. Manolis and colleagues will then use these assays to analyse candidate epilepsy genes identified previously in human studies. This analysis will act as a proof-of-principle study to validate the Drosophila platform to replace the use of mouse studies in both basic and clinical epilepsy research.
Epilepsy is a debilitating and potentially lethal human condition that affects ~1% of the population. The associated costs of care for patients make it the second neurological condition in terms of burden to the NHS.
Moreover, the epilepsy field is currently being transformed by the impact of genomic studies that are revealing the genetic underpinnings of rare congenital epilepsies often co-morbid with ataxic and sleep disturbances. The large number of candidate loci identified by such studies clearly necessitates the generation of corresponding animal models to confirm the causal connection between mutations in such genes and epileptic seizures. In epilepsy research this almost invariably means rodents.
Drosophila is an ideal organism to test the influence of gene variants on a neurological condition, including polygenic conditions. However, the fly is under-utilized in epilepsy research.
In this application we plan to overcome the obstacles to a full uptake of Drosophila as an alternative and 3Rs-beneficial model for studying epilepsy. Specifically, our scientific aims will be:
1) To develop a methodology for confidently assessing seizures in adult flies. This will include hardware and software development for bioassays to analyse behaviour and neural activation in seizures.
2) To provide proof of principle studies that validate the use of this methodology. This will include analysis of Epg5-Snap25 interactions, of genes linked to Kcna1 and that may ameliorate seizures in Dravet syndrome and generalised epilepsy with febrile seizures, as well as testing ~10 candidate genes identified in human studies by collaborating clinical geneticists.
Through collaboration with project partners and supporting top UK clinical epilepsy genetics, and through a number of pro-active dissemination activities, we aim to facilitate the uptake of flies in epilepsy research, at least to the same level in which they are used in neurodegeneration research.