Modeling Fragile X Syndrome in Drosophila

描述（由申请人提供）： 脆性X综合征是人类智力迟钝的最常见遗传形式之一，发病率为1/4000男性和1/6000女性。它是由FMR 1基因功能丧失引起的。脆性X综合征患者患有多种症状，包括：智力迟钝、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。身体缺陷包括巨大睾丸和不规则树突棘形态。在以前的研究中，我们的实验室在果蝇中开发了一个脆性X模型。该模型基于dfmr 1（也称为dfxr）基因，该基因与FMR 1基因具有高度的序列同一性/相似性。dFMR 1蛋白与FMR 1蛋白（FMRP）具有相似的RNA结合特性、发育表达模式和亚细胞分布。在最近的研究中，我们已经表明，dfmr 1无效突变体显示几个行为缺陷，承担脆性X患者的症状相似。果蝇的相关表型包括昼夜节律行为、求偶时注意力缺陷、记忆缺陷和神经元形态的细微缺陷。dFMR 1和FMRP的生物化学性质的相似性及其功能表型的丧失表明，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dfmr 1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FMR 1活性何时以及如何发挥作用，以防止认知和行为缺陷。目前尚不清楚FMR 1的时间要求和分子作用。我们建议使用果蝇模型的脆性X，以确定何时需要dfmr 1活性，以确定是否是由于发育或生理缺陷的行为缺陷。我们也在研究dfmr 1功能丧失可能影响的生理途径。通过这些研究，我们已经确定了一种药物治疗方法，可以挽救我们的dfmr 1突变体中显示的求爱和记忆缺陷。在本提案中，我们将确定并验证该药物的作用途径，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.