Department of Biology, University of Alabama, Box 870344, Tuscaloosa, AL 35487-0344, USA.
Neurobiol Dis. 2011 Mar;41(3):669-77. doi: 10.1016/j.nbd.2010.12.001. Epub 2010 Dec 13.
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 orthologue, 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.
天使综合征 (AS) 和自闭症谱系障碍 (ASD) 的潜在缺陷部分可能是由于突触可塑性和功能的基本缺陷。在某些个体中，可减少 5-羟色胺前突触再摄取的选择性 5-羟色胺再摄取抑制剂，以及可阻断多巴胺和 5-羟色胺受体的利培酮，可改善症状。UBE3A 基因母源性表达缺失导致 AS，而包含 UBE3A 基因的 15q11.2-q13 染色体母源性重复导致 ASD，提示母源性表达的 UBE3A 基因与 ASD 表型有关。在一个通过 UBE3A 筛选蛋白的果蝇筛选中，我们鉴定出一种单胺合成的关键调节剂，即基因 Punch 或 GCH1，编码酶 GTP 环水解酶 I。在这里，我们显示果蝇 UBE3A 同源物 Dube3a 调节果蝇大脑中的 Punch/GCH1。Dube3a 的过表达可提高四氢生物蝶呤 (THB)，即单胺合成的限速辅因子，而 Dube3a 的缺失则有相反的效果。多巴胺水平的波动分别与果蝇的过度活跃和活动不足有关。我们表明，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，在核部分中均发现高水平的野生型 Dube3a 和泛素化缺陷型 Dube3a-C/A 形式，并且它们似乎在体内被内源性 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的 GCH1 活性。这些结果提供了单胺合成（多巴胺/5-羟色胺）与 Dube3a 表达之间的联系，这可能解释为什么一些 ASD 或 AS 患者对选择性 5-羟色胺再摄取抑制剂的反应比其他人更好。
