Phagocytosis is misregulated in a Drosophila model of Fragile X syndrome

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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.