The role of UBE3A in gliopathic seizures

仅在美国就有多达300万人患有癫痫发作。虽然某些形式的癫痫 虽然癫痫患者对抗癫痫药物的反应很好，但很大一部分癫痫患者并不 对药物或饮食治疗反应良好。一种研究潜在的分子和细胞 癫痫病的病理学是通过研究遗传学定义的综合征，其中癫痫是突出特征。 大约25-50%的重复15 q综合征（Dup 15 q）患者难以控制 癫痫发作解释Dup 15 q癫痫发作的流行假设是母体特异性神经元升高， 泛素E3连接酶UBE 3A和/或位于UBE 3A附近的GABA受体基因簇的复制 在15q11.2-q13.1。利用我们实验室的果蝇进行的研究表明， 癫痫发作可能是由神经胶质中UBE 3A水平升高引起的，而不是如先前提出的神经元。前提 因为这一观点认为癫痫发作是由神经胶质细胞中UBE 3A蛋白水平升高引起的，而不是神经元， 不仅为Dup 15 q相关癫痫的分子机制提供了一条途径，而且也是一种范式转变， 神经胶质细胞与癫痫的病因直接相关。本提案中概述的实验旨在 研究过表达Dube 3a的胶质细胞的发育时间和分子变化， 揭示了这些变化如何在我们开发的一种新的小鼠模型中重现，该模型在神经胶质细胞中表达Ube 3a。 细胞我们从这些苍蝇研究中了解到的一切将直接传播给一个癫痫发作专家小组 他们在全国各地的复制15 q卓越中心工作。查明新 Dup 15 q癫痫的治疗靶点也可能为患有癫痫的个体提供新的治疗选择。 对目前的抗癫痫药具有药物抗性。

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.