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.

Public Health Relevance

Autism is often associated with misregulated immune system function. The most common monogenic cause of autism is Fragile X syndrome;I found that dFMR1 mutants, a Drosophila model of Fragile X syndrome with well-established neurological symptoms, exhibited altered phagocytosis by immune cells. Because misregulated immune system function is hypothesized to play a role in etiology or progression of autism, this proposal further investigates the role of dFMR1 in regulating phagocytosis by immune cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS080673-01A1
Application #
8658238
Study Section
NST-2 Subcommittee (NST)
Program Officer
Mamounas, Laura
Project Start
2013-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$47,232
Indirect Cost
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032