Mutations in the mitochondrially-encoded ATP6 subunit of the ATP synthase protein complex cause human mitochondrial encephalomyopathies including maternally inherited Leigh Syndrome (MILS), neuropathy, ataxia, and retinitis pigmentosa (NARP), and familial bilateral striatal necrosis (FBSN). Symptoms of these devastating progressive disorders include shortened lifespan, neurodegeneration, organ system failure, and seizures. No cures have been found, and effective treatment of the symptoms has proven difficult. For example, the seizures present in these diseases are often refractory to common anti-epileptic drugs (AEDs). Recently, a point mutation affecting the ATP6 subunit has been identified and characterized in Drosophila melanogaster. This mutant line, termed ATP6[1], shares the progressive pathological features of the above disorders, thus providing one of the only stable animal models of mitochondrial disease that can be studied throughout the animal's lifetime. Using patch clamp electrophysiology on whole-brain explants from adult ATP6[1] flies, we have found that the well-characterized large lateral ventral neurons (l-LNv) of the Drosophila circadian and sleep circuits exhibit hyperexcitability, including elevated interspik membrane potential and firing frequency, and increased responses to excitatory stimuli including direct light exposure and depolarizing current injections. This makes them an excellent model neuron for the study of the seizures associated with mitochondrial diseases. Our preliminary data suggests the altered excitability may be due to multiple factors, which include changes in both membrane channels present in the l-LNv and in synaptic inputs. We propose to use these well- characterized and electrophysiologically-accessible neurons to identify these channel subunits and synaptic contributions, so that upon completion of this work we will know the relevant molecular contributors which may ultimately become therapeutic targets for the seizures of mitochondrial disease.
Seizures affect approximately 50% of patients of mitochondrial disease, which translates to tens of thousands of people worldwide. Patients are often unresponsive to currently available anti-epileptic drugs, which contributes to a reduced quality of life and is associated with a poor prognosis. We propose to use our stable animal model of mitochondrial disease and a powerful combined genetic and elctrophysiological approach to elucidate pathogenesis of metabolically-linked seizures, which is the first step toward opening up new therapeutic avenues.
| Fogle, Keri J; Hertzler, J Ian; Shon, Joy H et al. (2016) The ATP-sensitive K channel is seizure protective and required for effective dietary therapy in a model of mitochondrial encephalomyopathy. J Neurogenet 30:247-258 |
