Animal Models For Studying Angelman Syndrome, A Developmental Brain Disorder

天使人综合症是一种严重的大脑发育障碍，其特征是智力迟钝、癫痫发作、步态异常、多动、频繁笑和其他异常。一些证据有力地表明，在大多数（如果不是全部的话）天使人综合征病例中，母体人类Ube3A （hUbe3A）基因的缺失。Ube3A编码E6-AP泛素E3连接酶，其底物大部分未知。UbeSA活性丧失如何导致Angelman综合征患者的临床症状有待进一步研究。在果蝇基因组中，基因CG6190编码果蝇Ube3A (dUbeSA)，这是一种在氨基酸水平上与hUbeSA高度同源的蛋白。因此，果蝇提供了一个很好的模型系统来解剖Ube3A的分子和细胞功能。在这里，我们提出验证UbeSA对于神经元精细结构的正确形成和神经元连接的正常发育是必需的这一假设。这些神经发育过程的缺陷可能与天使综合征的发病机制有关。我们将产生dUbeSA功能缺失突变果蝇，并表征dUbeSA在神经元发育中的功能。我们还将利用这些突变果蝇来鉴定一些进化保守的UbeSA泛素连接酶的关键底物，这些底物介导UbeSA对大脑发育和功能的影响。这些研究将为这种破坏性发育性脑障碍的分子和细胞机制提供重要见解，并为治疗干预提供潜在途径。格拉德斯通神经疾病研究所，J. David Gladstone研究所，旧金山，加州PHS 398 （Rev. 09/04）第2页表格第2页3首席研究员/项目主任（最后，第一，中）：高，奋标

Angelman syndrome is a severe developmental brain disorder characterized by mental retardation, seizures, abnormal gait, hyperactivity, frequent laughter, and other abnormalities. Several lines of evidence strongly implicate the loss of the maternal human Ube3A (hUbe3A) gene in most, if not all, cases of Angelman syndrome. Ube3A encodes the E6-AP ubiqutin E3 ligase whose substrates remain largely unknown. How the loss of UbeSA activity leads to clinical symptoms of Angelman syndrome patients needs further investigation. In the Drosophila genome, the gene CG6190 encodes the Drosophila Ube3A (dUbeSA), a protein highly homologous to hUbeSA at the amino acid level. Therefore, Drosophila offers an excellent model system to dissect the molecular and cellular functions of Ube3A. Here we propose to test the hypothesis that UbeSA is required for the proper formation of neuronal fine structures and for the normal development of neuronal connectivity. The defects in these neurodevelopmental processes may contribute to the pathogenesis of Angelman syndrome. We will generate dUbeSA loss-of-function mutant flies and characterize dUbeSA function in neuronal development. We will also use these mutant flies to identify some evolutionary conserved key substrates of UbeSA ubiquitin ligase that mediate the effects of UbeSA on the brain development and function. These studies will provide important insights into the molecular and cellular mechanisms underlying this devastating developmental brain disorder and into the potential avenues for therapeutic interventions. Gladstone Institute of Neurological Disease, The J. David Gladstone Institutes, San Francisco, CA PHS 398 (Rev. 09/04) Page 2 Form Page 2 3 Principal Investigator/Program Director (Last, First, Middle): Gao, Fen-BiaO KEY