Animal Models For Studying Angelman Syndrome, A Developmental Brain Disorder

安格曼综合征是一种严重的大脑发育障碍，其特征为智力低下、癫痫发作、步态异常、多动、频繁大笑和其他异常。多项证据强烈表明，在大多数（如果不是全部）天使综合征病例中，母体人类 Ube3A (hUbe3A) 基因的丢失。 Ube3A 编码 E6-AP 泛素 E3 连接酶，其底物仍然很大程度上未知。 UbeSA活性丧失如何导致Angelman综合征患者的临床症状需要进一步研究。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高度同源的蛋白质。因此，果蝇提供了一个优秀的模型系统来剖析 Ube3A 的分子和细胞功能。在这里，我们建议检验以下假设：UbeSA 是神经元精细结构的正确形成和神经元连接的正常发育所必需的。这些神经发育过程的缺陷可能导致天使综合征的发病机制。我们将生成 dUbeSA 功能丧失突变体果蝇，并表征 dUbeSA 在神经元发育中的功能。我们还将使用这些突变果蝇来鉴定 UbeSA 泛素连接酶的一些进化保守的关键底物，这些底物介导 UbeSA 对大脑发育和功能的影响。这些研究将为了解这种破坏性发育性脑部疾病的分子和细胞机制以及治疗干预的潜在途径提供重要见解。格拉德斯通神经疾病研究所，J. David Gladstone 研究所，旧金山，加利福尼亚州 PHS 398（修订版 09/04） 第 2 页 表格第 2 页 3 首席研究员/项目主任（姓、名、中）：Gao, Fen-BiaO KEY

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