Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism.
Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism.
复制标题
DOI：
10.1016/j.nbd.2010.12.001
复制
发表时间：
2011-03
影响因子：
6.1
通讯作者：
Reiter, Lawrence T.
中科院分区：
文献类型：
--
作者：
Ferdousy, Faiza;Bodeen, William;Summers, Kyle;Doherty, Olugbenga;Wright, O'Neil;Elsisi, Nahed;Hilliard, George;O'Donnell, Janis M.;Reiter, Lawrence T.
关键词：
Angelman综合征（AS）和自闭症谱系障碍（ASD）的潜在缺陷可能部分归因于突触可塑性和功能的基本缺陷。在一些个体中，血清素再摄取抑制剂可以减少突触前血清素的再摄取，可以改善症状，利培酮也可以，它可以阻断多巴胺和血清素受体。母体UBE3A表达缺失导致AS，而母体包含UBE3A基因的染色体15q11.2-q13重复导致ASD，提示母体表达的UBE3A基因参与ASD表型。在果蝇中筛选由UBE3A调节的蛋白质，我们发现了单胺合成的关键调节因子，基因Punch，或GCH1，编码GTP环水解酶i。这里我们表明Dube3a，苍蝇UBE3A的同源物，调节苍蝇大脑中的Punch/GCH1。Dube3a的过表达提高了四氢生物蝶呤（THB），这是单胺合成的限速辅助因子，而Dube3a的缺失具有相反的作用。在果蝇中，多巴胺水平的波动分别与多动症和多动症有关。我们发现Punch/GCH1和多巴胺水平的变化不依赖于Dube3a的泛素连接酶催化结构域。此外，野生型Dube3a和泛素化缺陷的Dube3a- c / a形式在细胞核中都有高水平的存在，并且在体内似乎被内源性Dube3a多泛素化。我们提出Dube3a的转录共激活功能可能调节大脑中GCH1的活性。这些结果提供了单胺合成（多巴胺/血清素）和Dube3a表达之间的联系，这可能解释了为什么一些ASD或AS患者对选择性血清素再摄取抑制剂的反应比其他人更好。
The underlying defects in Angelman syndrome (AS) and autism spectrum disorder (ASD) may be in part due to basic defects in synaptic plasticity and function. In some individuals serotonin reuptake inhibitors, which decrease pre-synaptic re-uptake of serotonin, can ameliorate symptoms, as can resperidone, which blocks both dopamine and serotonin receptors. Loss of maternal UBE3A expression causes AS, while maternal duplications of chromosome 15q11.2-q13 that include the UBE3A gene cause ASD, implicating the maternally expressed UBE3A gene in the ASD phenotype. In a Drosophila screen for proteins regulated by UBE3A, we identified a key regulator of monoamine synthesis, the gene Punch, or GCH1, encoding the enzyme GTP cyclohydrolase I. Here we show that Dube3a, the fly UBE3A ortholog, regulates Punch/GCH1 in the fly brain. Over-expression of Dube3a elevates tetrahydrobiopterin (THB), the rate-limiting cofactor in monoamine synthesis while loss of Dube3a has the opposite effect. The fluctuations in dopamine levels were associated with hyper- and hypoactivity, respectively, in flies. We show that changes in Punch/GCH1 and dopamine levels do not depend on the ubiquitin ligase catalytic domain of Dube3a. In addition, both wild type Dube3a and a ubiquitination-defective Dube3a-C/A form were found at high levels in nuclear fractions and appear to be poly-ubiquitinated in vivo by endogenous Dube3a. We propose that the transcriptional co-activation function of Dube3a may regulate GCH1 activity in the brain. These results provide a connection between monoamine synthesis (dopamine/serotonin) and Dube3a expression that may explain why some individuals with ASD or AS respond better to selective serotonin reuptake inhibitors than others.
登录
查看更多内容
影响因子：
4.8
作者：
Funderburk, Christopher D.;Bowling, Kevin M.;O'Donnell, Janis M.
通讯作者：
O'Donnell, Janis M.
影响因子：
4.4
作者：
Cummings, Edwin D.;Brown, Janet M.;Hilliard, George M.
通讯作者：
Hilliard, George M.
多巴胺水平的增加增强了果蝇的雄性求爱。
影响因子：
5.3
作者：
Liu, Tong;Dartevelle, Laurence;Guo, Aike
通讯作者：
Guo, Aike
影响因子：
1.9
作者：
Krishnakumar, S;Burton, D;O'Donnell, J
通讯作者：
O'Donnell, J
影响因子：
2
作者：
Descheemaeker, MJ;Govers, V;Fryns, JP
通讯作者：
Fryns, JP