The role of UBE3A in gliopathic seizures

仅在美国就有多达300万人患有癫痫发作。尽管某些形式的癫痫 对抗癫痫药物的反应相当好，相当一部分癫痫患者不能 对药物或饮食治疗反应良好。研究潜在分子和细胞的一种方法 癫痫的病理学是通过研究一种基因定义的综合征来进行的，其中癫痫是一个突出的特征。 大约25%-50%的重复15q综合征患者(Dup15q)难以控制 癫痫发作。解释Dup15q癫痫发作的流行假说是母体特异性神经元抬高。 泛素E3连接酶UBE3A和/或与UBE3A相邻的一组GABA受体基因的重复 在15q11.2-q13.1。使用我们实验室的果蝇进行的研究表明，这些 癫痫发作可能是由胶质细胞中UBE3A水平升高引起的，而不是之前提出的神经元。前提是 对于这一提议，癫痫是由胶质细胞中UBE3A蛋白水平升高引起的，而不是神经元， 这不仅为Dup15q相关癫痫的分子机制提供了途径，而且也是一种范式的转变。 直接表明神经胶质细胞与癫痫的病因有关。这份提案中概述的实验是设计的 探讨高表达Dube3a的神经胶质细胞的发育时间和分子变化 揭示这些变化是如何在我们开发的一种新的小鼠模型中概括的，该模型在胶质细胞中表达Ube3a 细胞。我们从这些苍蝇研究中学到的一切都将直接传播给一个癫痫专家团队 他们在全国范围内的15Q卓越复制中心工作。新产品的识别 Dup15q癫痫的治疗目标也可能为符合以下条件的个人提供新的治疗选择 对当前的抗癫痫药物产生抗药性。

As many as ~3 million individuals suffer from epileptic seizures in the US alone. Although some forms of epilepsy respond quite well to anti-seizure medications, a substantial portion of individuals suffering from epilepsy do not respond well to medication or dietary treatments. One way to investigate the underlying molecular and cellular pathology of seizure disorder is by studying a genetically defined syndrome where epilepsy is a prominent feature. Approximately 25-50% of individuals with Duplication 15q syndrome (Dup15q) suffer from difficult to control seizures. The prevailing hypotheses to explain seizures in Dup15q are maternal specific neuronal elevation of the ubiquitin E3 ligase UBE3A and/or duplication of a cluster of GABA receptor genes located adjacent to UBE3A at 15q11.2-q13.1. Studies using the fruit fly, Drosophila melanogaster, from our laboratory indicates that these seizures may be caused by elevated levels of UBE3A in glia, not neurons as previously proposed. The premise for this proposal is that seizures are caused by elevated levels of the UBE3A protein in glia, not neurons, providing not only a pathway to molecular mechanism for Dup15q related epilepsy, but also a paradigm shift, directly implicating glial cells in the etiology of seizures. The experiments outlined in this proposal are designed to investigate the developmental timing and molecular changes in glial cells over-expressing Dube3a and to reveal how these changes are recapitulated in a new mouse model we developed that expresses Ube3a in glial cells. Everything we learn from these studies in flies will be directly disseminated to a team of seizure experts who work at the Duplication 15q centers of excellence throughout the country. The identification of new therapeutic targets for Dup15q epilepsy may also provide new treatment options to individuals who are pharmacoresistant to current anti-epileptics.