Mutation of orthologous prickle genes causes a similar epilepsy syndrome in flies and humans.
Mutation of orthologous prickle genes causes a similar epilepsy syndrome in flies and humans.
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DOI：
10.1002/acn3.334
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发表时间：
2016-09
影响因子：
5.3
通讯作者：
Manak, J. Robert
中科院分区：
文献类型：
--
作者：
Ehaideb, Salleh N.;Wignall, Elizabeth A.;Kasuya, Junko;Evans, William H.;Iyengar, Atulya;Koerselman, Haley L.;Lilienthal, Anthony J.;Bassuk, Alexander G.;Kitamoto, Toshihiro;Manak, J. Robert
遗传学上易于控制的果蝇几十年来一直被用来研究癫痫发作。然而，有一个具体相关的苍蝇和人类癫痫发作表型的数据很少。我们先前已经证明，从苍蝇到人类的正向PRICKLE基因突变会导致癫痫发作。本研究旨在确定苍蝇中的刺痛介导的癫痫发作表型是否与PRICKLE患者中发现的癫痫综合征密切相似。几乎所有的苍蝇癫痫发作研究都依赖于诱发癫痫发作的特征。我们已经开发了两种新的方法来更精确地表征棘突突变果蝇在其天然状态下的癫痫发作相关表型。首先，我们使用高分辨率录像记录自发的、无端的癫痫发作事件。其次，我们开发了一种运动协调试验，以评估是否刺痛突变苍蝇共济失调。第三，我们用左乙拉西坦处理突变果蝇，以确定其行为表型是否可以被一种常见的抗癫痫药物抑制。我们发现，棘突突变苍蝇表现出肌阵挛样自发性癫痫发作事件，并严重共济失调。这两种表型都在PRICKLE突变的人类患者中发现，并且可以被左乙拉西坦抑制，这提供了表型是由于神经功能障碍的证据。这些结果首次记录了高分辨率的苍蝇人类癫痫发作障碍模型中自发的、无端的癫痫发作事件，捕获了自然状态下的癫痫发作。总的来说，这些数据强调了苍蝇和人类PRICKLE介导的癫痫综合征之间的惊人相似性，并为解剖人类综合征表型的根本原因提供了一个遗传学上易于处理的模型。
Genetically tractable fruit flies have been used for decades to study seizure disorders. However, there is a paucity of data specifically correlating fly and human seizure phenotypes. We have previously shown that mutation of orthologous PRICKLE genes from flies to humans produce seizures. This study aimed to determine whether the prickle‐mediated seizure phenotypes in flies closely parallel the epilepsy syndrome found in PRICKLE patients. Virtually all fly seizure studies have relied upon characterizing seizures that are evoked. We have developed two novel approaches to more precisely characterize seizure‐related phenotypes in their native state in prickle mutant flies. First, we used high‐resolution videography to document spontaneous, unprovoked seizure events. Second, we developed a locomotion coordination assay to assess whether the prickle mutant flies were ataxic. Third, we treated the mutant flies with levetiracetam to determine whether the behavioral phenotypes could be suppressed by a common antiepileptic drug. We find that the prickle mutant flies exhibit myoclonic‐like spontaneous seizure events and are severely ataxic. Both these phenotypes are found in human patients with PRICKLE mutations, and can be suppressed by levetiracetam, providing evidence that the phenotypes are due to neurological dysfunction. These results document for the first time spontaneous, unprovoked seizure events at high resolution in a fly human seizure disorder model, capturing seizures in their native state. Collectively, these data underscore the striking similarities between the fly and human PRICKLE‐mediated epilepsy syndromes, and provide a genetically tractable model for dissecting the underlying causes of the human syndromic phenotypes.
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影响因子：
12.3
作者：
Cook RK;Christensen SJ;Deal JA;Coburn RA;Deal ME;Gresens JM;Kaufman TC;Cook KR
通讯作者：
Cook KR
影响因子：
4.5
作者：
Boumil, Rebecca M.;Letts, Verity A.;Frankel, Wayne N.
通讯作者：
Frankel, Wayne N.
影响因子：
2.7
作者：
Cardenas, F;Lamprea, MR;Morato, S
通讯作者：
Morato, S
影响因子：
3.7
作者：
Colomb J;Reiter L;Blaszkiewicz J;Wessnitzer J;Brembs B
通讯作者：
Brembs B
DOI：
10.1534/g3.113.006130
发表时间：
2013-08-07
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Howlett IC;Rusan ZM;Parker L;Tanouye MA
通讯作者：
Tanouye MA