title: The ATP-sensitive K channel is seizure protective and required for effective dietary therapy in a model of mitochondrial encephalomyopathy.
abstract: Effective therapies are lacking for mitochondrial encephalomyopathies (MEs). MEs are devastating diseases that predominantly affect the energy-demanding tissues of the nervous system and muscle, causing symptoms such as seizures, cardiomyopathy, and neuro- and muscular degeneration. Even common anti-epileptic drugs which are frequently successful in ameliorating seizures in other diseases tend to have a lower success rate in ME, highlighting the need for novel drug targets, especially those that may couple metabolic sensitivity to neuronal excitability. Furthermore, alternative epilepsy therapies such as dietary modification are gaining in clinical popularity but have not been thoroughly studied in ME. Using the Drosophila ATP61model of ME, we have studied dietary therapy throughout disease progression and found that it is highly effective against the seizures of ME, especially a high fat/ketogenic diet, and that the benefits are dependent upon a functional KATPchannel complex. Further experiments with KATPshow that it is seizure-protective in this model, and that pharmacological promotion of its open state also ameliorates seizures. These studies represent important steps forward in the development of novel therapies for a class of diseases that is notoriously difficult to treat, and lay the foundation for mechanistic studies of currently existing therapies in the context of metabolic disease.
authors.affiliation: a Department of Pharmacology & Chemical Biology , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.|b Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Keri J
authors.initials: KJ
authors.lastname: Fogle
authors.affiliation: a Department of Pharmacology & Chemical Biology , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.|b Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: J Ian
authors.initials: JI
authors.lastname: Hertzler
authors.affiliation: a Department of Pharmacology & Chemical Biology , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.|b Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Joy H
authors.initials: JH
authors.lastname: Shon
authors.affiliation: a Department of Pharmacology & Chemical Biology , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.|b Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Palladino
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D055423:Diet, Ketogenic; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D017237:Mitochondrial Encephalomyopathies / Q000150:complications / Q000178:diet therapy* / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D015221:Potassium Channels; D025261:Mitochondrial Proton-Translocating ATPases; C569734:mt:ATPase6 protein, Drosophila
keywords: ATP6; Drosophila; mitochondria; seizure