Drosophila parabss Flies as a Screening Model for Traditional Medicine: Anticonvulsant Effects of Annona senegalensis

Dare, Samuel Sunday; Merlo, Emiliano; Curt, Jesús Rodríguez; Ekanem, Peter E.; Hu, Nan; Berni, Jimena

doi:10.3389/fneur.2020.606919

Cited by 10 publications

(18 citation statements)

References 44 publications

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“…The rather unexacting approach of candidate compound screening in Drosophila also facilitates broader application and is less cost-intensive than in other models. It also allows for exploring less conventional treatments, e.g., agents used in traditional medicine ( Dare et al, 2020 ).…”

Section: Drosophila Genetics and Tools To Investigate Seizur...mentioning

confidence: 99%

Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview

Fischer

Karge²,

Weber³

et al. 2023

Front. Mol. Neurosci.

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Epilepsy is one of the most prevalent neurological disorders, affecting more than 45 million people worldwide. Recent advances in genetic techniques, such as next-generation sequencing, have driven genetic discovery and increased our understanding of the molecular and cellular mechanisms behind many epilepsy syndromes. These insights prompt the development of personalized therapies tailored to the genetic characteristics of an individual patient. However, the surging number of novel genetic variants renders the interpretation of pathogenetic consequences and of potential therapeutic implications ever more challenging. Model organisms can help explore these aspects in vivo. In the last decades, rodent models have significantly contributed to our understanding of genetic epilepsies but their establishment is laborious, expensive, and time-consuming. Additional model organisms to investigate disease variants on a large scale would be desirable. The fruit fly Drosophila melanogaster has been used as a model organism in epilepsy research since the discovery of “bang-sensitive” mutants more than half a century ago. These flies respond to mechanical stimulation, such as a brief vortex, with stereotypic seizures and paralysis. Furthermore, the identification of seizure-suppressor mutations allows to pinpoint novel therapeutic targets. Gene editing techniques, such as CRISPR/Cas9, are a convenient way to generate flies carrying disease-associated variants. These flies can be screened for phenotypic and behavioral abnormalities, shifting of seizure thresholds, and response to anti-seizure medications and other substances. Moreover, modification of neuronal activity and seizure induction can be achieved using optogenetic tools. In combination with calcium and fluorescent imaging, functional alterations caused by mutations in epilepsy genes can be traced. Here, we review Drosophila as a versatile model organism to study genetic epilepsies, especially as 81% of human epilepsy genes have an orthologous gene in Drosophila. Furthermore, we discuss newly established analysis techniques that might be used to further unravel the pathophysiological aspects of genetic epilepsies.

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Section: Drosophila Genetics and Tools To Investigate Seizur...mentioning

confidence: 99%

Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview

Fischer

Karge²,

Weber³

et al. 2023

Front. Mol. Neurosci.

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“…La epilepsia es un trastorno neurológico con crisis espontáneas y recurrentes que se producen por una hiperexcitación y/o desincronización en los circuitos neuronales (Dare et al, 2021, Catterall, 2018. Es un trastorno común que afecta a un porcentaje entre 1% y 3% de la población mundial, lo cual equivale a aproximadamente 50 millones de personas (Dare et al, 2021), y puede ser debida a factores genéticos o adquiridos.…”

Section: Epilepsia Y Canalopatíasunclassified

“…La epilepsia más común o de causa genética también se llama idiopática. Su herencia es compleja, desde mutaciones monogenéticas hasta oligogénicas (Dare et al, 2021). Dentro de este grupo, las mutaciones en canales son las más comunes y están asociadas a gran cantidad de patologías (Deconinck et al, 2009).…”

Section: Epilepsia Y Canalopatíasunclassified

“…Existen multitud de herramientas para la manipulación genética y la generación de modelos en D.melanogaster. La mutación para bss1 por ejemplo, no es equivalente a ninguna mutación humana, pero presenta un fenotipo muy similar al del síndrome de Dravet, por lo que se usa como modelo de esta y otra epilepsias intratables (Dare et al, 2021;L. Parker, Padilla, et al, 2011).…”

Section: Drosophila Melanogasterunclassified

“…Se escogió este modelo porque el modelo para KO generado y caracterizado en capítulos anteriores es nulo, y por tanto solo serviría para la búsqueda de modificadores supresores, pero no de intensificadores. Las crisis del modelo para bss1 presentan una fase tónico-clónica y son las más difíciles de suprimir tanto genética como farmacológicamente hablando (Dare et al, 2021;L. Parker, Padilla, et al, 2011).…”

Section: Modelo Para Bss1unclassified

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Generación de nuevos modelos y búsqueda de modificadores para el Síndrome de Dravet en Drosophila Melanogaster

González¹

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Dravet syndrome is a severe rare epileptic disease caused by mutations in the SCN1A gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. In this thesis we have made a new mutation in a gene called para KO through homologous recombination, the single Drosophila melanogaster gene encoding this type of protein.These flies showed a heat-induced seizing phenotype, and sudden death in long term seizures. In addition to seizures, neuromuscular alterations were observed in climbing, flight and locomotion tests. Moreover, they also manifested some cognitive alterations such as anxiety and difficulties in learning. Using magnets as a therapy for epileptic phenotype, seizures start was delayed, and its duration and the quantity of flies affected was lower.Metabolomic profile of these flies' brains showed an increase in the amount of aminoacids, succinate and lactate, alterations that could be related with epilepsy and mitochondrial dysfunction. GABA, the main neurotransmitter involved in Dravet syndrome, was higher in the para KO model. Electrophysiological sodium current analysis from aCC motoneurons in larvae stage revealed an increase in persistent currents and their ratio with transients, which is a symptom for epileptic seizures. Cell XV ABREVIATURAS Y ACRÓNIMOS Aa: aminoácidos Ach: acetilcolina ADN: ácido desoxirribonucleico ARN: ácido ribonucleico ARNdc: ácido ribonucleico de doble cadena ARNi: ácido ribonucleico interferente ARNm: ácido ribonucleico mensajero BDSC: centro de stock de Drosophila melanogaster en Bloomington BS: sensible a ''bang'' C. elegans: Caenorhabditis elegans Cac: ''cacophony'' CACNA1A: subunidad α1 A del canal dependiente de voltaje de calcio CHRNA4: subunidad α4 del receptor de acetilcolina CHRNB2: subunidad β2 del receptor de acetilcolina CLCN1: proteína 1 del canal de voltaje de cloro Clc-α: canal de cloro alfa CyO: ''curly of oster'' DGRP: panel de referencia genético de Drosophila melanogaster D. melanogaster: Drosophila melanogaster XVI DM: Drosophila melanogaster DNasa: desoxiribonucleasa GABA: ácido aminobutírico GAL4: factor de transcripción sensible a galactosa GEFS+: epilepsia generalizada con crisis febriles plus HD: dominios de homología iPSC: células madre de pluripotencia inducida Kb: kilobases KCNQ: subfamilia Q de los canales de potasio dependientes de voltaje KCNQ3 : subfamilia de los canales de potasio dependientes de voltaje KO: ''knock-out'' nAChRα1: receptor nicotínico α1 de acetilcolina nAChRα4: receptor nicotínico α1 de acetilcolina Nav: canal de sodio dependiente de voltaje Nipagín: methyl 4-hydroxybenzoato NMJ: uniones neuromusculares P21: 21 días post-natales para: ''paralitic'' para bss1 : gen ''paralitic'' con alelo ''bang'' sensitive PAX6: ''paired box 6'' PCA: análisis de componentes principales XVII PCR: reacción en cadena de la polimerasa PCRc: reacción en cadena de la polimerasa cuantitativa PV: parvalbúmina positivas rcf: fuerza centrífuga relativa RMN: resonancia magnética nuclear RNasa: ribonucleasa rp49: proteína ribosomal L32...

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Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures

Lu¹,

Hernan²,

Marcogliese³

et al. 2022

The American Journal of Human Genetics

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Drosophila parabss Flies as a Screening Model for Traditional Medicine: Anticonvulsant Effects of Annona senegalensis

Cited by 10 publications

References 44 publications

Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview

Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview

Generación de nuevos modelos y búsqueda de modificadores para el Síndrome de Dravet en Drosophila Melanogaster

Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures

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