Animal Models For Studying Angelman Syndrome, A Developmental Brain Disorder

Angelman综合征是一种严重的发育性脑障碍，其特征为智力迟钝、癫痫发作、异常步态、多动、频繁大笑和其他异常。几条证据强烈暗示在大多数（如果不是全部）Angelman综合征病例中母体人类Ube 3A（hUbe 3A）基因的丢失。Ube 3A编码E6-AP泛素E3连接酶，其底物在很大程度上仍然未知。UbeSA活性的丧失如何导致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CG 6190编码果蝇Ube 3A（dUbeSA），其是在氨基酸水平上与hUbeSA高度同源的蛋白质。因此，果蝇提供了一个很好的模型系统来剖析Ube 3A的分子和细胞功能。在这里，我们建议测试的假设，UbeSA是必要的神经元精细结构的正确形成和神经元连接的正常发展。这些神经发育过程中的缺陷可能有助于Angelman综合征的发病机制。我们将产生dUbeSA功能丧失突变果蝇，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UbeSA泛素连接酶的一些进化上保守的关键底物，这些底物介导UbeSA对大脑发育和功能的影响。这些研究将为这种破坏性发育性脑障碍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。Gladstone神经疾病研究所，J.大卫格莱斯顿研究所，San弗朗西斯科，CA PHS 398（Rev. 09/04）第2页表格第2页3主要研究者/项目负责人（最后，第一，中间）：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