Synaptic Actin Signaling Pathways in Fragile X

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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Compound that Inhibits mGluR5 Corrects Signs of Fragile X in Adult Mice

A study finds that a new compound reverses many of the major symptoms associated with Fragile X syndrome (FXS). The paper is published in the April 12 issue of the journal Neuron, describing the exciting observation that the FXS correction can occur in adult mice, after the symptoms of the condition have already been established. Previous research has suggested that inhibition of mGlu5, a subtype of receptor for the excitatory neurotransmitter glutamate, may ameliorate many of the major symptoms of the disease. This study, a collaboration between a group at Roche in Switzerland, led by Dr. Lothar Lindemann, and Dr. Mark Bear’s MIT lab, used an mGlu5 inhibitor called CTEP to examine whether inhibition of mGlu5 could reverse FXS symptoms.

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Role of JNK in FMRP Regulated Translation in Fragile X Syndrome

Role of JNK in FMRP Regulated Translation in Fragile X Syndrome

With a $90,000 grant from FRAXA Research Foundation over 2 years, Dr. Michael Wilhelm and his team at the University of Wisconsin studied a protein known as JNK, which is observed to be abnormally regulated in Fragile X. Like FMRP, it is involved in regulating dendritic protein synthesis, and so it may be a target for drug therapy in Fragile X.

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Role of Excessive Protein Synthesis in the Ontogeny of FXS

Role of Excessive Protein Synthesis in the Ontogeny of FXS

With a $90,000 grant from FRAXA Research Foundation in 2010-2011, Dr. Mark Bear and Dr. Miquel Bosch tested the simple hypothesis that the excessive rate of protein synthesis is not a consequence but the primary cause of the structural alterations occurring in Fragile X syndrome.

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Manipulating Basal and mGluR-Stimulated cAMP Level in FXS Model Mice

Manipulating Basal and mGluR-Stimulated cAMP Level in FXS Model Mice

With a $90,000 grant from FRAXA Research Foundation, Dr. Hongbing Wang’s team from Michigan State University looked at a treatment target “downstream” of the mGluR5 called cyclic AMP (cAMP). Levels of cAMP are lower in FXS patients and animal models, suggesting that it plays a role in FXS. Drugs that raise levels of cAMP may effectively treat Fragile X. We are very pleased to report that, in 2012, Dr. Wang received a 5-year, $250,000 per year R01 grant from NIH to continue this promising research.

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The Role of FMRP and Small, Non-Coding RNAs in Translation

The Role of FMRP and Small, Non-Coding RNAs in Translation

With a $120,000 grant from FRAXA Research Foundation, Drs. Henri Tiedge and Jun Zhong studied the mechanisms by which local protein translation is repressed. Multiple parallel mechanisms keep protein synthesis in check; one of them involves FMRP, and a similar mechanism involves the non-coding RNA, BC1. Results published.

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Understanding the Mechanism of mGluR5 in Fragile X Mouse Models

Understanding the Mechanism of mGluR5 in Fragile X Mouse Models

With $184,000 in funding from FRAXA Research Foundation from 1996-2005, Dr. Ben Oostra and his team at Erasmus University have done multiple studies related to Fragile X syndrome. This lab created the first Fragile X mouse models and went on to perform many critical studies in Fragile X mouse models. Results published.

Drs. Oostra, Warren, and Nelson discovered the Fragile X gene and its FRAXA mutation in 1991.Read more

Developing Fragile X Treatments in Fruit Flies and Mice

Developing Fragile X Treatments in Fruit Flies and Mice

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.

Sean McBride, PhD, Albert Einstein College of Medicine, FRAZA research grantRead more

The miRNA Pathway in Fragile X Syndrome

With a $120,000 grant from FRAXA Research Foundation over 2008-2009, Drs. Oostra and deVrij at Erasmus University studied miRNA and Fragile X. miRNAs are RNAs that can repress the translation of target mRNAs – therefore they can play a role in protein synthesis within the neuron. Preliminary results showed large differences in miRNA expression in the Fragile X mouse brain compared to the wild type. This lab investigated the effect of mGluR5 antagonists on the levels of these specific miRNAs.

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Imaging Synaptic Structure and Function in Fragile X Mice

Imaging Synaptic Structure and Function in Fragile X Mice

FRAXA Research Foundation grants $150,000 over 2005-2009 to Dr. Carlos Portera-Cailliau to study intact, anesthetized Fragile X mouse brains, looking for defects in the density, length, or dynamics of the dendrites. They looked for changes in the neurons after treatment with mGluR5 antagonists.

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Role of Matrix Metalloproteinases (MMP-9) in Fragile X

Role of Matrix Metalloproteinases (MMP-9) in Fragile X

With a $220,000 grant from FRAXA Research Foundation over 3 years, Dr. Iryna Ethell from the University of California at Riverside studied the regulation of dendritic structure by matrix metalloproteinases and other extracellular signaling pathways. This work identified a major treatment strategy for Fragile X with the available MMP-9 inhibitor, minocycline.

Iryna Ethell, PhD, at University of CaliforniaRead more

Basic Mechanisms of Disease and Potential Therapeutic Strategies

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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Glutamate Metabolism in Fragile X Mouse Brain

Glutamate Metabolism in Fragile X Mouse Brain

With a $95,000 grant from FRAXA Research Foundation over 2 years, Mary McKenna at the University of Maryland studied the role of metabotropic glutamate receptors (mGluR) and how they affect other cells and pathways.

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Targeting the Role of Group 1 Metabotropic Glutamate Receptors

Targeting the Role of Group 1 Metabotropic Glutamate Receptors

With a $40,000 grant from FRAXA Research Foundation in 2008, Dr. Huibert Mansvelder and his team at the University of Amsterdam studied the role of different receptors and their reactions to drug compounds.

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Regulation of Group I Metabotropic Glutamate Receptor Trafficking in Fragile X

Regulation of Group I Metabotropic Glutamate Receptor Trafficking in Fragile X

With an $83,500 grant from FRAXA Research Foundation in 2005 and 2007, Dr. Anna Fracesconi at Albert Einstein College studied the patterns and pathways of different receptors related to Fragile X.

Anna Francesconi, PhD, at Albert Einstein College of Medicine, FRAXA research grantRead more

Decreased Excitatory Drive onto Parvalbumin-Positive Neocortical Inhibitory Neurons in a Mouse Model of Fragile X Syndrome

Decreased Excitatory Drive onto Parvalbumin-Positive Neocortical Inhibitory Neurons in a Mouse Model of Fragile X Syndrome

With an $80,000 grant from FRAXA Research Foundation over 2006-7, Drs. Jay Gibson and Kimberly Huber at the University of Texas at Southwestern examined if the defected inhibitory neurotransmission was a primary or secondary symptom of Fragile X to determine where future treatment targets should be focused.

Jay Gibson, PhD, at University of Texas at Southwestern, FRAXA research grantRead more

Electrophysiological, Biochemical and Immunohistochemical Characterization of Kv3.1 in Auditory Brainstem Nuclei in the Fragile X Knockout Mouse

Electrophysiological, Biochemical and Immunohistochemical Characterization of Kv3.1 in Auditory Brainstem Nuclei in the Fragile X Knockout Mouse

With $80,000 in funding from FRAXA over several years, the Yale University team of Leonard Kaczmarek, PhD showed that loss of FMRP leads to an increased Kv3.1 potassium currents. This change impairs timing of action potentials in auditory neurons (and likely others throughout the brain).

Leonard Kaczmarek, PhDRead more

Metabotropic Glutamate Receptor Function in Fragile X Knockout Mice

Metabotropic Glutamate Receptor Function in Fragile X Knockout Mice

With $143,000 in grants from FRAXA Research Foundation from 2004-2006, Drs. Walter Kaufmann, Richard Huganier, Paul Worley, and David Lieberman at Johns Hopkins University studied the molecular dynamics of mGluRs in areas involved in cognition in the Fragile X knockout mouse.

Walter Kaufman, MD, PhD, at Johns Hopkins University, FRAXA research grantRead more

Pharmacologic Interventions in the Fmr1 KO Mouse

Pharmacologic Interventions in the Fmr1 KO Mouse

With $48,600 in grants from FRAXA Research Foundation over 2004-2006, Dr. Catherine Choi at Drexel University studied Fragile X knockout mice to determine future treatment targets for Fragile X syndrome in humans.

Catherine Choi, Drexel University, FRAXA research grantRead more

Role of Experience in Regulating Levels of the Fragile X Protein

Role of Experience in Regulating Levels of the Fragile X Protein

FRAXA awarded $29,000 in 2001 and $20,000 in 2000 to Kenneth J. Mack, MD, PhD — Mayo Clinic with Peter K. Todd, MD, PhD, Postdoctoral Fellow. While a professor at University of Wisconsin-Madison, Dr. Mack investigated whether and how FMRP levels are regulated in response to neuronal stimulation in vivo (in live animals). He looked at the effects of seizures and of experience in his experiments. Dr. Mack and colleagues published their findings.

Kenneth J. Mack, MD, PhD, at Mayo Clinic, FRAXA research grantRead more

Treatment of a Mouse Model of Fragile X Syndrome with MPEP

Treatment of a Mouse Model of Fragile X Syndrome with MPEP

With a $49,000 grant from FRAXA Research Foundation in 2003, Dr. Linda Crnic at the University of Colorado continued studies of MPEP in Fragile X mice, exploring whether chronic use improves symptoms of Fragile X syndrome without impairing cognitive function.

Linda Crnic, PhD, at University of Colorado, FRAXA research grantRead more

Synaptic Plasticity and Olfactory Learning in Fragile X

Synaptic Plasticity and Olfactory Learning in Fragile X

With a $40,000 grant from FRAXA Research Foundation in 2000, Dr. John Larson and his team at the University of Illinois Chicago used olfaction (sense of smell) in mice as a neuro-behavioral model system for human memory. They characterized olfactory sensitivity, learning, and memory in FMR1 knockout mice as compared to wild-type (normal control) mice.

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