Fragile X Mutant Mouse Models

David Nelson, PhD, FRAXA Investigator

With $375,000 in grants from the FRAXA Research Foundation since 2009, Dr. David Nelson has developed an impressive array of advanced mouse models of Fragile X, at Baylor College of Medicine. These models are available to investigators worldwide on request. This resource has been essential for a broad, rapid distribution of Fragile X and related gene mouse models and has increased the pace of Fragile X research.

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Repurposing Drugs to Dampen Hyperactive Nonsense-Mediated Decay in Fragile X Syndrome

With a $90,000 grant from the FRAXA Research Foundation, Dr. Lynne Maquat and Dr. Tatsuaki Kurosaki will investigate nonsense-mediated mRNA decay (NMD) in Fragile X. NMD is a “housekeeping” process that cells use to prevent faulty proteins from being made. But there is too much of it in Fragile X syndrome. There are already available drugs that suppress NMD – including caffeine.

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FRAXA Grant to Nahum Sonenberg, PhD — Effects of metformin in Fmr1 knockout mouse model of Fragile X syndrome

Nahum Sonenberg

Mis-regulation of activity-dependent protein synthesis is one of the major cellular abnormalities found in Fragile X. Upstream neuronal signaling regulates a large cluster of enzymes called the mTORC1 complex, which in turn regulates protein synthesis. This complex is also controlled by cellular energy levels via the metabolic sensor AMP-activated Protein Kinase (AMPK). AMPK is a highly conserved kinase that is activated under conditions of energy stress, when intracellular ATP levels decline and intracellular AMP increases.

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Scientists Uncover Trigger for Fragile X Syndrome

Samie Jaffrey, PhD, at Weill Medical College of Cornell University, FRAXA research grant

A new study led by Weill Cornell Medical College scientists shows that Fragile X syndrome occurs because of a mechanism that shuts off the gene associated with the disease. The findings, published today in Science, also show that a compound that blocks this silencing mechanism can prevent Fragile X syndrome – suggesting a similar therapy may be possible for 20 other diseases that range from mental retardation to multisystem failure.

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Small Molecules To Target r(CGG) Expansions to Treat Fragile X Syndrome

With a 2-year, $90,000 grant from FRAXA Research Foundation, Dr.’s Matthew Disney and Wang-Yong Yang worked to correct the underlying problem in Fragile X: the silencing of the Fragile X gene (FMR1) and the resulting lack of FMRP (Fragile X Mental Retardation Protein). Their approach was to use novel small molecules to target the abnormal CGG repeats before the FMR1 gene.

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Fragile X Syndrome Protein Linked to Breast Cancer Progression

Claudia Bagni (VIB/KU Leuven, Belgium, and the University of Rome, Italy) and colleagues have identified the way Fragile X Mental Retardation Protein or FMRP contributes to the progression of breast cancer. The researchers demonstrated that FMRP acts as a master switch controlling the levels of several proteins involved in different stages of aggressive breast cancer, including the invasion of cancer cells into blood vessels and the spread of these cancer cells to other tissues forming metastasis.

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Synaptic Actin Signaling Pathways in Fragile X

With a $163,356 grant from FRAXA Research Foundation in 2010-12, Dr. Scott Soderling and Dr. Hwan Kim at Duke University bred the standard mouse model of Fragile X syndrome to their lines of mice that express reduced levels of several key proteins that modulate synaptic actin. These compound mutant mice were compared to FXS mice to determine if genetically impairing pathways to the actin cytoskeleton can rescue deficits in the FXS mice.

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Inherited Channelopathies in Cortical Circuits of Fmr1 KO Mice

Andreas Frick, PhD

With this two year award of $90,000, Dr. Zhang and Principal Investigator Dr. Andreas Frick at Neurocentre Magendie in France investigated channelopathies using Fragile X mice. Many other proteins are misregulated as a result of the absence of FMRP. It is known that many ion channels, the pores in the cell membrane which allow neurons to conduct electrical impulses, have altered levels in Fragile X. This state is sometime called a “channelopathy” in the pharma world. This group is studying the effect of specific alterations in ion channels, and potential therapeutic effects of drugs which open and close these channels.

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Composition and Localization of Dendritic mRNAs in Fragile X Syndrome

With a $80,000 grant from FRAXA Research Foundation over 2 years, Drs. Smith and Wang are investigating which proteins, as well as the mRNA’s that code those proteins, are dysregulated in Fragile X. They have developed a elegant system to visualize the proteins and mRNA’s and determine where they are spacially in the neuron. This will help to better understand the root causes of Fragile X syndrome and to design targeted treatments.

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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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