From bench to drug: Human seizure modeling using Drosophila

Song, Juan; Tanouye, Mark A.

doi:10.1016/j.pneurobio.2007.10.006

Cited by 89 publications

(87 citation statements)

References 71 publications

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“…One of the hallmarks of bang-sensitive mutants is the induction of the phenotype with electrical stimulation (Song and Tanouye 2008). High-frequency stimulation of the sda iso7.8 resulted in an initial seizure followed by a recovery seizure, as has been previously reported (Zhang et al 2002).…”

Section: Seizure Phenotypesupporting

confidence: 59%

“…A variety of model organisms have been used to study the genetic causes of epilepsy, including zebrafish (Cunliffe 2016) and Drosophila (Song and Tanouye 2008). Behavioral screens in Drosophila have identified mutants and the underlying genes that cause a "bang-sensitive" (BS) behavioral phenotype, that is, they paralyze and seize following mechanical or electrical stimulation (Pavlidis et al 1994;Lee and Wu 2002;Fergestad et al 2006;Parker et al 2010).…”

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confidence: 99%

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julius seizure, a Drosophila Mutant, Defines a Neuronal Population Underlying Epileptogenesis

et al. 2017

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Epilepsy is a neural disorder characterized by recurrent seizures. Bang-sensitive Drosophila represent an important model for studying epilepsy and neuronal excitability. Previous work identified the bang-sensitive gene slamdance (sda) as an allele of the aminopeptidase N gene. Here we show through extensive genetic analysis, including recombination frequency, deficiency mapping, transposon insertion complementation testing, RNA interference (RNAi), and genetic rescue that the gene responsible for the seizure sensitivity is julius seizure (jus), formerly CG14509, which encodes a novel transmembrane domain protein. We also describe more severe genetic alleles of jus. RNAi-mediated knockdown of jus revealed that it is required only in neurons and not glia, and that partial bang-sensitivity is caused by knockdown in GABAergic or cholinergic but not glutamatergic neurons. RNAi knockdown of jus at the early pupal stages leads to strong seizures in adult animals, implicating that stage as critical for epileptogenesis. A C-terminal-tagged version of Jus was generated from a fosmid genomic clone. This fosmid fusion rescued the bang-sensitive phenotype and was expressed in the optic lobes and the subesophageal and thoracic abdominal ganglia. The protein was primarily localized in axons, especially in the neck connectives, extending into the thoracic abdominal ganglion.

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Section: Seizure Phenotypesupporting

confidence: 59%

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confidence: 99%

julius seizure, a Drosophila Mutant, Defines a Neuronal Population Underlying Epileptogenesis

et al. 2017

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“…Because many AS patients experience seizures, we also subjected dube3a mutant flies to mechanical stress by vortexing them or heat shocking them briefly. Subjecting the flies to mechanical or thermal stress induces paralysis in susceptible flies, a phenomenon that is thought to be related to human seizures (44). dube3a mutant flies of two ages were subjected to each stress, and none of the flies showed any signs of paralysis (data not shown).…”

Section: Flies With Dube3a Mutations Are Defective In Long-term Memorymentioning

confidence: 99%

A Drosophila model for Angelman syndrome

Bolduc

Bell

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Angelman syndrome is a neurological disorder whose symptoms include severe mental retardation, loss of motor coordination, and sleep disturbances. The disease is caused by a loss of function of UBE3A, which encodes a HECT-domain ubiquitin ligase. Here, we generate a Drosophila model for the disease. The results of several experiments show that the functions of human UBE3A and its fly counterpart, dube3a, are similar. First, expression of Dube3a is enriched in the Drosophila nervous system, including mushroom bodies, the seat of learning and memory. Second, we have generated dube3a null mutants, and they appear normal externally, but display abnormal locomotive behavior and circadian rhythms, and defective long-term memory. Third, flies that overexpress Dube3a in the nervous system also display locomotion defects, dependent on the ubiquitin ligase activity. Finally, missense mutations in UBE3A alleles of Angelman syndrome patients alter amino acid residues conserved in the fly protein, and when introduced into dube3a, behave as loss-of-function mutations. The simplest model for Angelman syndrome is that in the absence of UBE3A, particular substrates fail to be ubiquitinated and proteasomally degraded, accumulate in the brain, and interfere with brain function. We have generated flies useful for genetic screens to identify Dube3a substrates. These flies overexpress Dube3a in the eye or wing and display morphological abnormalities, dependent on the critical catalytic cysteine. We conclude that dube3a mutants are a valid model for Angelman syndrome, with great potential for identifying the elusive UBE3A substrates relevant to the disease.

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“…A Drosophila model for seizure disorders has been presented on the basis of a collection of 34 neurological mutants that affect seizure susceptibility, including seizure-sensitive and seizure-suppressor mutants (Song and Tanouye 2008). This study evaluates the mutant bang senseless (bss 1 ) as an intractable epilepsy extension to the model.…”

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confidence: 99%

Drosophila as a Model for Epilepsy:bssIs a Gain-of-Function Mutation in the Para Sodium Channel Gene That Leads to Seizures

et al. 2011

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We report the identification of bang senseless (bss), a Drosophila melanogaster mutant exhibiting seizure-like behaviors, as an allele of the paralytic (para) voltage-gated Na 1 (Na V ) channel gene. Mutants are more prone to seizure episodes than normal flies because of a lowered seizure threshold. The bss phenotypes are due to a missense mutation in a segment previously implicated in inactivation, termed the ''paddle motif'' of the Na V fourth homology domain. Heterologous expression of cDNAs containing the bss 1 lesion, followed by electrophysiology, shows that mutant channels display altered voltage dependence of inactivation compared to wild type. The phenotypes of bss are the most severe of the bang-sensitive mutants in Drosophila and can be ameliorated, but not suppressed, by treatment with anti-epileptic drugs. As such, bss-associated seizures resemble those of pharmacologically resistant epilepsies caused by mutation of the human Na V SCN1A, such as severe myoclonic epilepsy in infants or intractable childhood epilepsy with generalized tonic-clonic seizures.

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From bench to drug: Human seizure modeling using Drosophila

Cited by 89 publications

References 71 publications

julius seizure, a Drosophila Mutant, Defines a Neuronal Population Underlying Epileptogenesis

julius seizure, a Drosophila Mutant, Defines a Neuronal Population Underlying Epileptogenesis

A Drosophila model for Angelman syndrome

Drosophila as a Model for Epilepsy:bssIs a Gain-of-Function Mutation in the Para Sodium Channel Gene That Leads to Seizures

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