Using the Social Amoeba Dictyostelium as a biomedical model: An innovative approach to help children with intractable epilepsy
Brief Abstract:
Epilepsy is a severe neurological disorder where 30% of patients continue to experience seizures despite treatment, with research predominantly involving animals. We have developed a replacement model for this research, the social amoeba Dictyostelium discoideum, to discover a mechanism of action for a common anti-epileptic drug. This enabled us to identify more potent compounds including a fat, found in coconuts, that is used in a dietary treatment for drug-resistant epilepsy. From this, we have demonstrated that the compound rapidly blocks seizure activity, and have developed an improved diet for children with drug resistant epilepsy that is currently in clinical trials.
Full Abstract:
Our research has focused on employing the social amoeba Dictyostelium as a simple model system for biomedical research. The model provides a range of advantages in this role including rapid growth, single and multiple cell stages, well characterised development, rapid genetic ablation or protein tagging and the use of isogenic cultures. Here we will outline a long-standing research area in our laboratory concerning epilepsy, initiated in Dictyostelium and translated to mammalian systems. Our studies initial employed Dictyostelium to better understand the molecular mechanisms of the commonly used epilepsy treatment, valproic acid. We showed that, in Dictyostelium, the drug blocked turnover of phosphoinositides, and were able to show a similar effect in the mammalian brain during seizure progression. Using this effect in Dictyostelium, we then identified a range of compounds with enhanced activity. One of these compounds, decanoic acid, is a major constituent of a diet used to treat drug resistant epilepsy, called the medium chain triglyceride (MCT) ketogenic diet. We then showed that decanoic acid, which is elevated in the plasma of patients on the diet, acts to directly control seizure activity in multiple seizure models, and this effect is not shown for ketones, suggesting that the diet may not act via ketogenesis. We further identified a primary target for decanoic acid, in this therapeutic role. From this work, clinical trials are now underway for the treatment of both children and adults with intractable epilepsy using a new ketogenic diet derived from this work.
This projects therefore highlights the use of Dictyostelium as a simple and malleable model system for biomedical research, and successful translation to clinical studies.