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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Genetic and Pharmacologic Manipulation of PI3K Activity in FXS: Assessing Potential Therapeutic Value

Genetic and Pharmacologic Manipulation of PI3K Activity in FXS: Assessing Potential Therapeutic Value

With a $90,000 grant from the FRAXA Research Foundation, Dr. Gary Bassell and his team at Emory University explored the PI3K/mTOR signaling complex in FXS via genetic and pharmacologic rescue approaches, to reduce the enzymatic function of specific components of this complex pathway in an FXS mouse model.

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Inherited Channelopathies in Cortical Circuits of Fmr1 KO Mice

Inherited Channelopathies in Cortical Circuits of Fmr1 KO Mice

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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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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Altered Dendritic Synthesis of Postsynaptic Scaffold Protein Shank1 in Fragile X Syndrome

Altered Dendritic Synthesis of Postsynaptic Scaffold Protein Shank1 in Fragile X Syndrome

With a $106,800 grant from FRAXA Research Foundation over 2 years, Drs. Stephan Kindler and Hans-Jurgen Kreieinkamp studied a protein, Shank1, which is overabundant in Fragile X syndrome.

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The Slack Potassium Ion channel is a Therapeutic Target for Fragile X

The Slack Potassium Ion channel is a Therapeutic Target for Fragile X

With $282,000 in funding from FRAXA Research Foundation, Dr. Leonard Kaczmarek and colleagues explored association of Slack channels with the Fragile X protein (FMRP).

Leonard Kaczmarek, PhDRead more

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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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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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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Role of FMRP in the Regulation of Synaptic Plasticity

Role of FMRP in the Regulation of Synaptic Plasticity

With more than $1,000,000 from FRAXA Research Foundation over 13 years, Drs. William Greenough and Ivan-Jeanne Weiler at the University of Illinois uncovered the role of FMRP at synapses, leading to much of the subsequent research on Fragile X syndrome.

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Using Fenobam to Reduce APP and Abeta in Fragile X Mice

Using Fenobam to Reduce APP and Abeta in Fragile X Mice

With a $130,000 grant from FRAXA Research Foundation over 2008-2009, Drs. James Malter and Cara Westmark at the University of Wisconsin studied the relationship between the Fragile X protein FMRP and APP, a protein important to the pathology of Alzheimer’s Disease. APP may also contribute to the pathology of Fragile X, and its major metabolite, Aß, may contribute to abnormal protein synthesis via a positive feedback loop. This project sought to restore normal dendritic protein synthesis in Fragile X mice by breaking into this loop.

James Malter, at University of Wisconsin-Madison, 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

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

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

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.

Yong Zhang, PhD, at Chinese Academy of Sciences, FRAXA research grantRead more

Splicing Variations of the Fragile X Gene

Splicing Variations of the Fragile X Gene

With an $80,000 grant from FRAXA Research Foundation from 2005-2006, Dr. David Morris and his team at the University of Washington aimed to understand the variation in distribution and function of FMRP isoforms, sought to identify isoforms of FMRP in mouse brain, and define the expression pattern of these versions of the protein.

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Drosophila CYFIP, a Molecular Link Between Actin Cytoskeleton Remodeling and Fragile X

Drosophila CYFIP, a Molecular Link Between Actin Cytoskeleton Remodeling and Fragile X

With $130,000 in funding from FRAXA Research Foundationfrom 2004-2006, Dr. Angela Giangrande at the Universite Louis Pasteur investigated the interactions between dendrites, messenger mRNA, and the cytoskeleton in fruit flies, which are a simple yet powerful system in which multiple genes can be manipulated with relative ease.

Angela Giangrande, PhD, Universite Louis Pasteur, FRAXA research grantRead more

Genetic and Behavioral Analyses of the dFMR1 Pathway in Drosophila Peripheral Nervous System

Genetic and Behavioral Analyses of the dFMR1 Pathway in Drosophila Peripheral Nervous System

With a $160,000 grant from FRAXA Research Foundation from 2004-2006, Dr. Fen-Biao Gao and his team at the University of California studied the relationship between mRNA and FMRP.

Fen-Biao Gao, PhD, at University of California at San Fransico, FRAXA research awardRead more

Role of MicroRNAs in Fragile X Syndrome

Role of MicroRNAs in Fragile X Syndrome

With a $70,000 grant from FRAXA Research Foundation from 2004-2005, Drs. Thomas Tuschl and Neil Renwick and their team at Rockefeller University researched how FMRP interacts with miRNA in order to determine more effective treatment targets for Fragile X syndrome.

Thomas Tuschl, PhD, at Rockefeller University, FRAXA research grantRead more

DFXR and Synaptic Tagging in Drosophila (Fruit Flies)

DFXR and Synaptic Tagging in Drosophila (Fruit Flies)

With a $135,000 grant from FRAXA Research Foundation from 2001-2003, Dr. Jerry Yin and his team at the University of Wisconsin researched memory formation in Fragile X fruit flies. Dr. Yin started his Fragile X studies at Cold Spring Harbor Laboratory before moving to the Waisman Center.

Jerry Yin, PhD, at University of Wisconsin, FRAXA research grantRead more

Understanding the Function of Fragile X Protein in Drosophila

Understanding the Function of Fragile X Protein in Drosophila

With a $105,000 grant from FRAXA Research Foundation from 2000-2003, Drs. Haruhiko Siomi and Mikko Siomi at Tokushima University researched approaches to characterize the Drosophila homolog of FMR1 and its associated molecules, and to identify molecular pathways that are involved in the cellular processes which are affected by the loss-of-function of Drosophila FMR1.

Haruhiko Siomi, PhD, at Tokushima University, FRAXA research grantRead more