Interdisciplinary Graduate Program in Genetics University of Iowa Iowa City Iowa; King Abdullah International Medical Research Cente rKing Abdulaziz Medical City Riyadh Saudi Arabia; Department of Biology University of Iowa Iowa City Iowa.
Department of Biology University of Iowa Iowa City Iowa.
Ann Clin Transl Neurol. 2016 Aug 3;3(9):695-707. doi: 10.1002/acn3.334. eCollection 2016 Sep.
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.
几十年来，遗传上可操作的果蝇一直被用于研究癫痫发作障碍。然而，与果蝇和人类癫痫发作表型相关的数据却很少。我们之前已经表明，从果蝇到人类的同源 PRICKLE 基因突变会引起癫痫发作。本研究旨在确定果蝇中 PRICKLE 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关。
几乎所有的果蝇癫痫发作研究都依赖于对诱发的癫痫发作进行特征描述。我们开发了两种新方法，以更精确地描述 PRICKLE 突变果蝇中固有状态下与癫痫发作相关的表型。首先，我们使用高分辨率录像来记录自发的、无诱因的癫痫发作事件。其次，我们开发了一种运动协调测定法来评估 PRICKLE 突变果蝇是否共济失调。第三，我们用左乙拉西坦处理突变果蝇，以确定这些行为表型是否可以被一种常见的抗癫痫药物所抑制。
我们发现 PRICKLE 突变果蝇表现出类似于肌阵挛的自发癫痫发作事件，并且严重共济失调。这两种表型都存在于 PRICKLE 基因突变的人类患者中，并且可以被左乙拉西坦抑制，这提供了证据表明这些表型是由于神经功能障碍引起的。这些结果首次在果蝇人类癫痫发作障碍模型中以高分辨率记录自发、无诱因的癫痫发作事件，在其自然状态下捕获癫痫发作。
这些数据共同强调了果蝇和人类 PRICKLE 介导的癫痫综合征之间的惊人相似之处，并为剖析人类综合征表型的潜在原因提供了一个遗传上可操作的模型。
