Modeling Fragile X Syndrome in Drosophila

描述(由申请人提供)： 脆性X综合征是人类最常见的遗传性智力低下形式之一，发病率为每4000名男性和每6000名女性中有1名。这是由于FMR1基因功能丧失所致。脆性X综合征患者患有各种症状，包括智力低下、注意力缺陷、多动、睡眠障碍、焦虑、情绪不稳定和自闭症样行为。生理缺陷包括大症和不规则树突棘形态。在之前的研究中，我们的实验室在果蝇身上开发了脆性X模型。这个模型基于dfmr1(也称为dfxr)基因，它与FMR1基因具有高度的序列同源性/相似性。DFMR1蛋白具有与FMR1蛋白(FMRP)相似的RNA结合特性、发育表达模式和亚细胞分布。在最近的研究中，我们发现dfmr1缺失突变体表现出几种行为缺陷，与脆性X患者的症状相似。果蝇的相关表型包括心律失常的昼夜节律行为、求偶时的注意力缺陷、记忆缺陷和神经元形态的细微缺陷。DFMR1和FMRP在生化性质上的相似性以及它们的功能丧失表型表明，这两种蛋白在相似的行为和发育过程中具有保守的功能。因此，果蝇dfmr1突变体是研究脆性X综合征的相关模型。为了改善脆性X综合征，我们必须了解FMR1活动何时以及如何发挥作用，以预防认知和行为缺陷。FMR1的时间需求和分子作用目前尚不清楚。我们建议使用脆性X的果蝇模型来确定何时需要dfmr1活性来确定行为缺陷是由发育缺陷还是生理缺陷引起的。我们还在研究dfmr1功能丧失可能影响的生理通路。通过这些研究，我们已经确定了一种药物治疗，可以挽救我们的dfmr1突变体中表现出的求爱和记忆缺陷。在这项提案中，我们将确定和验证该药物的作用路线，以确定治疗脆性X综合征的潜在靶点。

DESCRIPTION (provided by applicant): Fragile X syndrome is one of the most commonly inherited forms of human mental retardation with an incidence rate of 1 in 4000 males and 1 in 6000 females. It is caused by the loss of FMR1 gene function. Patients with Fragile X syndrome suffer from a variety of symptoms including; mental retardation, attention deficit, hyperactivity, sleep disorders, anxiety, unstable mood and autistic-like behaviors. Physical defects include macroorchidism and irregular dendritic spine morphology. In previous studies, our lab developed a Fragile X model in Drosophila. This model is based on the dfmr1 (also called dfxr) gene, which has a high degree of sequence identity/similarity to the FMR1 gene. The dFMR1 protein has similar RNA binding properties, developmental expression pattern and subcellular distribution to the FMR1 protein (FMRP). In recent studies, we have shown that dfmr1 null mutants display several behavioral defects that bear similarity to symptoms of Fragile X patients. The relevant phenotypes in Drosophila include arrhythmic circadian behavior, attention deficit during courtship, memory defects and subtle defects of neuronal morphology. The similarities in the biochemical properties of dFMR1 and FMRP and their loss of function phenotypes suggest that these two proteins have conserved function in similar behavioral and developmental processes. Thus the Drosophila dfmr1 mutants are a relevant model to study aspects of Fragile X syndrome. To ameliorate Fragile X syndrome it is imperative that we understand when and how FMR1 activity functions to prevent cognitive and behavioral defects. The temporal requirements and molecular role of FMR1 are currently not known. We propose to use the Drosophila model of Fragile X to determine when dfmr1 activity is required to determine if the behavioral defects are due to developmental or physiological defects. We are also investigating possible physiological pathways affected by loss of dfmr1 function. Through these studies we have identified a pharmacological treatment that rescues the courtship and memory defects displayed in our dfmr1 mutants. In this proposal we will determine and verify a route of action of this drug to identify potential targets for the treatment of Fragile X syndrome.