Fruit Flies to Model and Test Fragile X Treatments

Dr. Tom Jongens and Dr. Sean McBride study Fragile X Fruit Flies

Dr. Jongens and his collaborators have found an insulin-like protein in the fly brain that is overexpressed in the Fragile X mutant fly, leading to increased activity of the insulin signaling pathway. Furthermore, they found that certain behavioral patterns in the Fragile X flies can be rescued by expressing the FX gene just in insulin producing neurons in the fly brain. In the mutant, there are other changes in the signaling pathways, including a decrease in cAMP and elevation in PI3K, mTOR, Akt and ERK activity. They now propose to study 2 medicines used for diabetes: pioglitazone (increases cAMP and decreases Akt and ERK) and metformin (inhibits mTOR), in flies and mice to validate the potential efficacy of these novel therapeutics for Fragile X.

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Developing Fragile X Treatments in Fruit Flies and Mice

Sean McBride, PhD, Albert Einstein College of Medicine, FRAZA research grant

With a $380,000 grant from FRAXA Research Foundation from 2005-2009, Drs. Sean McBride, Tom Jogens, and Catherine Choi studied one of the most important aspects of FRAXA’s research; the preclinical validation of potential therapeutic strategies. Many labs have found new leads for treatment. However, very few have the capacity to test new drugs in the mouse model to establish efficacy rigorously enough to lead to clinical trials. The McBride lab (in a broad collaboration with the Choi, Jongens, and Skoulakis groups) aims to do just that. Results published.

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Basic Mechanisms of Disease and Potential Therapeutic Strategies

With $245,000 in grants from FRAXA Research Foundation, Dr. Stephen Warren and his lab at Emory University studied all aspects of Fragile X syndrome, from the mechanisms of repeat expansion to high-throughput drug screens in the Drosophila model of Fragile X. The Warren lab made the original discovery of the Fragile X gene, FMR1, in collaboration with the Nelson and Oostra labs, and is recognized internationally as a leader in molecular genetics. Recent projects include establishment of induced pluripotent stem cell lines from Fragile X patients, and determination of other forms of mutation in the Fragile X gene, other than the most common trinucleotide repeat expansion.

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Hypothalamic Pituitary Adrenal (HPA) Axis Dysregulation in Fragile X Syndrome

Carolyn-Beebe-Smith

The hypothalamic pituitary adrenal (HPA) axis is our central stress response system. FRAXA Research Foundation awarded Dr. Carolyn B. Smith $62,000 in funding in 2005 to explore the HPA axis in Fragile X mice. The results of their study indicate that, in FVB/NJ mice, the hormonal response to and recovery from acute stress is unaltered by the lack of Fragile X mental retardation protein. Results published.

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Defining Functional Domains of FMRP and Uncovering its Partners via Large Scale Mutagenesis in Drosophila

Yong Zhang, PhD, at Chinese Academy of Sciences, FRAXA research grant

With $80,000 in funding from FRAXA Research Foundation in 2005 and in 2006, Dr. Yong Zhang and his team at the Chinese Academy of Sciences developed a way to find genes that suppress the Fragile X gene. FRAXA grants $40,000 (2006) and $40,000 (2005) by Xinda Lin show that FMRP is a widely expressed RNA-binding protein involved in RNA transport and translation. Intensive studies in the last decade have demonstrated that FMRP contains four RNA binding domains, but their actual functions are mostly untested. Meanwhile, a dozen or so protein partners and hundreds of mRNA targets interacting with FMRP have been identified, but again their functions are poorly understood.

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