Phagocytosis is misregulated in a Drosophila model of Fragile X syndrome

描述(申请人提供)：在人类中，FMR1功能丧失导致脆性X综合征，这是导致自闭症和智力残疾的最常见的单基因原因。自闭症和脆性X综合征都与免疫系统功能改变有关。长期以来，人们一直假设，大脑中调节不当的免疫细胞在自闭症和其他神经疾病的病因或进展中发挥了作用。然而，导致这些症状的分子机制却知之甚少。我们的实验室使用已建立的果蝇模型来研究脆性X综合征。FMR1基因在果蝇和脊椎动物中高度保守，在分子和功能水平上都是如此。与脆性X综合征患者类似，缺乏果蝇同源基因dFMR1的突变果蝇表现出神经系统症状，包括神经元结构的变化、学习和记忆障碍、昼夜节律丧失，或约24小时的生理振荡。DFMR1突变体的免疫系统功能以前没有被描述过。我的初步数据表明，dFMR1的缺失改变了两种免疫细胞的吞噬活性：免疫血细胞或巨噬细胞；以及大脑中的免疫细胞或神经胶质细胞。我推测，吞噬功能的这些变化是由昼夜节律的丧失引起的。DFMR1突变体，类似于许多自闭症患者，已经失去了他们的昼夜节律。我在之前的一篇文章中指出，巨噬细胞的吞噬作用是受昼夜节律调节的。在我的初步数据中，我显示dFMR1突变体已经失去了巨噬细胞吞噬功能的昼夜调节。这项研究dFMR1缺失的昼夜节律障碍和免疫功能的具体目的将是：(1)确定昼夜节律调节神经元中dFMR1功能的丧失是否与巨噬细胞吞噬功能改变有关；以及(2)定量确定dFMR1在神经细胞发育过程中调节胶质细胞吞噬功能的作用。为了支持减轻精神疾病负担的使命，我们预计我们的研究将引入一种新的模型，研究脆性X综合征的智力残疾和自闭症的原因，并可能在未来对该疾病的治疗方法产生影响。

DESCRIPTION (provided by applicant): In humans, loss of function of FMR1 causes Fragile X syndrome, the most common monogenic cause of autism and intellectual disability. Both autism and Fragile X syndrome are associated with altered immune system function. It has long been hypothesized that misregulated immune cells in the brain play a role either in the etiology or progression of autism and other neurological diseases. However, the molecular mechanisms driving these symptoms are poorly understood. Our lab uses an established Drosophila model to study Fragile X syndrome. The FMR1 gene is highly conserved between flies and vertebrates, both on the molecular and functional levels. Similar to patients with Fragile X Syndrome, mutant flies lacking the Drosophila homolog dFMR1 exhibit neurological symptoms, including changes in neuronal structure, learning and memory defects, and loss of circadian rhythms, or physiological oscillations with a ~24hr period. The immune system function of dFMR1 mutants has not previously been characterized. My preliminary data suggest that loss of dFMR1 alters phagocytic activity by two types of immune cells: immune blood cells, or macrophages; and immune cells in the brain, or glia. I hypothesize that these change in phagocytosis are caused by loss of circadian regulation. dFMR1 mutants, similar to many human patients with autism, have lost their circadian regulation. I showed in a previous publication that phagocytosis by macrophages is circadian-regulated. In my preliminary data, I show that dFMR1 mutants have lost circadian regulation of phagocytosis by macrophages. The Specific Aims of this proposal to investigate the roles of circadian dysfunction and immunity in the absence of dFMR1 will be: (1) to determine whether the loss of dFMR1 function in circadian regulatory neurons is responsible for altered phagocytosis by macrophages; and (2) to quantitatively determine the role of dFMR1 in regulating phagocytosis by glia during neuronal development. In support of the mission of reducing the burden of mental illness, we anticipate that our research will introduce a new model of the cause of intellectual disability and autism in Fragile X syndrome with possible future implications for therapeutic approaches to the disease.