In recent years, Drosophila has been extensively used as a model for multiple human diseases. The goals are to uncover fundamental biological principles underlying causes of human pathology. There is also the compelling prospect of novel therapeutics identified by the study of disease-causing genes followed by targeted drug development, or by establishing platforms for high-throughput drug screening. In this proposal, we investigate a Drosophila model of epilepsy based on a set of neurological mutants with seizure-disorders that resemble some human epilepsies. We utilize aspects of this model to address several issues important in the causes and cures of seizure disorder. We are particularly interested in epilepsy caused by mutation of the Na+ channel gene. In humans, such mutations are associated with three forms of epilepsy: GEFS+ (generalized epilepsy with febrile seizures plus), characterized by febrile seizures that persist beyond the age of 6y;SMEI (severe myoclonic epilepsy in infancy), an intractable epilepsy frequently resulting in convulsive status epilepticus;and ICEGTC (intractable childhood epilepsy with generalized tonic-clonic), an atypical SMEI that does not cause myoclonic seizures. In flies, severe seizure-like behaviors and electrical abnormalities are caused by the bss mutations. These have been recently mapped to the Drosophila Na+ channel gene para. Here, we propose to investigate comprehensively the role of Na+ channel mutations in Drosophila seizure-susceptibility and use bss mutations as substrates for identifying potential AED candidates by drug screening and by seizure-suppressor mutations.

Public Health Relevance

Neurological mutants in the fruit fly Drosophila are used to explore causes and cures for human epilepsy. In this proposal, we search for new anti-epileptic drugs with the potential for greater efficacy and fewer side effects than those presently available for epilepsy treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031231-17
Application #
8209121
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Riddle, Robert D
Project Start
1994-07-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
17
Fiscal Year
2012
Total Cost
$316,592
Indirect Cost
$102,217
Name
University of California Berkeley
Department
Public Health & Prev Medicine
Type
Schools of Earth Sciences/Natur
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Saras, Arunesh; Tanouye, Mark A (2016) Seizure Suppression by High Temperature via cAMP Modulation in Drosophila. G3 (Bethesda) 6:3381-3387
Saras, Arunesh; Tanouye, Mark A (2016) Mutations of the Calcium Channel Gene cacophony Suppress Seizures in Drosophila. PLoS Genet 12:e1005784
Kroll, Jason R; Wong, Karen G; Siddiqui, Faria M et al. (2015) Disruption of Endocytosis with the Dynamin Mutant shibirets1 Suppresses Seizures in Drosophila. Genetics 201:1087-102
Kroll, Jason R; Saras, Arunesh; Tanouye, Mark A (2015) Drosophila sodium channel mutations: Contributions to seizure-susceptibility. Exp Neurol 274:80-7
Howlett, Iris C; Rusan, Zeid M; Parker, Louise et al. (2013) Drosophila as a model for intractable epilepsy: gilgamesh suppresses seizures in para(bss1) heterozygote flies. G3 (Bethesda) 3:1399-407
Howlett, Iris C; Tanouye, Mark A (2013) Seizure-sensitivity in Drosophila is ameliorated by dorsal vessel injection of the antiepileptic drug valproate. J Neurogenet 27:143-50
Kroll, Jason R; Tanouye, Mark A (2013) Rescue of easily shocked mutant seizure sensitivity in Drosophila adults. J Comp Neurol 521:3500-7
Parker, Louise; Padilla, Miguel; Du, Yuzhe et al. (2011) Drosophila as a model for epilepsy: bss is a gain-of-function mutation in the para sodium channel gene that leads to seizures. Genetics 187:523-34
Parker, Louise; Howlett, Iris C; Rusan, Zeid M et al. (2011) Seizure and epilepsy: studies of seizure disorders in Drosophila. Int Rev Neurobiol 99:1-21
Hekmat-Scafe, Daria S; Mercado, Adriana; Fajilan, Adriel A et al. (2010) Seizure sensitivity is ameliorated by targeted expression of K+-Cl- cotransporter function in the mushroom body of the Drosophila brain. Genetics 184:171-83

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