Below please find lay abstracts and links to articles on Fragile X syndrome that were published in August 2005 in the journal Genes, Brain and Behavior. View the latest issues content here or get free email table of content alerts.

S. MOLDIN:
Understanding Fragile X syndrome: molecular, cellular and genomic neuroscience at the crossroads

Fragile X Syndrome (FXS) is the most common inherited form of human mental retardation, with an estimated prevalence of one in 4,000 boys and one in 8,000 girls. The responsible gene - fragile X mental retardation 1 (FMR1) - is located on the X chromosome and was cloned in 1991. Massively expanded CGG trinucleotide repeats within the noncoding portion of FMR1 that become abnormally hypermethylated result in the transcriptional silencing of the encoded mRNA binding protein, Fragile X Mental Retardation Protein (FMRP), and are the causative mutations in 99% of FXS patients. We are truly at a watershed in FXS research, as cutting edge tools and technologies in molecular, cellular and genomic neuroscience are brought to bear and implicate key molecules, pathways and circuits involved in its pathophysiology and etiology. This special issue includes five articles that succinctly review state-of-the-art research on the neurobiology of FXS, and provide a valuable framework to dissect the role of FMRP in the FXS disease process and in normal neural development. Symptomatic commonalities among FXS and other pervasive developmental disorders like autism and Rett syndrome may reflect an overlap in underlying neural circuits and pathways, and hence shared pathophysiologic mechanisms. This raises the intriguing possibility that new therapeutics developed to treat FXS also may have efficacy in treating aspects of autism and Rett syndrome. And herein lies the promise of a truly successful roadmap for translational research, in which converging basic research in molecular, cellular and genomic neuroscience across multiple model systems leads us in the direction of new therapeutics for complex human diseases.

J. C. DARNELL, O. MOSTOVETSKY & R. B. DARNELL:
FMRP RNA targets: identification and validation

Fragile-X syndrome is caused by the loss of the normal function of the Fragile X Mental Retardation protein (FMRP) in the body’s cells, particularly in the neurons of the brain. FMRP is a protein that binds to ribonucleic acid (RNA) in the cell, and it is the loss of this RNA-binding activity that leads to the disease. Identification of the specific RNA molecules to which FMRP binds is a key step in understanding the function of the protein and the cellular defects caused by its absence. Because RNA encodes a cell’s proteins in a process called translation, understanding the RNAs bound by FMRP will reveal the protein products of those RNAs that are being over- or underproduced, or produced at the wrong time or place in the cell. In this manuscript we discuss the current understanding of FMRP as an RNA binding protein, different approaches that have been taken to identify these FMRP RNA targets, and discuss the relevance of some of these approaches to FMRP biology. In addition, we present evidence that mutations (single amino acid changes) in two of the RNA-binding domains of FMRP (known as KH domains) reduce its ability to control the translation of RNA into protein, but that mutation of its third RNA-binding domain (termed an RGG-box) does not. This suggests that RNA binding by the RGG box of FMRP may mediate aspects of cellular RNA metabolism other than the translation of RNA into protein. For example, it may control the movement of RNA inside the cell and therefore control where proteins are made as opposed to how much protein is made.

L. N. ANTAR, J. B. DICTENBERG, M. PLOCINIAK, R. AFROZ & G. J. BASSELL:
Localization of FMRP-associated mRNA granules and requirement of microtubules for activity-dependent trafficking in hippocampal neurons

A major challenge for Fragile X research is to understand the normal function of FMRP in the brain. With this knowledge, one is then better equipped to design rationale pharmacologic treatments to compensate for the loss of FMRP. We know that FMRP is an mRNA binding protein. This means that FMRP may play a key role in gene expression, since mRNAs are the genetic intermediates between the DNA (gene) and the encoded protein. In addition, we know that FMRP is present at synapses in the brain. Synapses are the physical site where two neurons communicate using chemical and electrical signals. Excitatory synapses in the brain release the neurotransmitter (chemical) called glutamate. This type of synapse is critically involved in brain development, learning and memory. Other laboratories have shown that these synapses have both structural and functional defects in Fragile X. Dr. Bassell’s laboratory has developed microscopic imaging tools to permit the direct visualization of FMRP in live neurons and have been able to track the movements of FMRP along the dendrites to the site of the synapse. This was done first by using recombinant DNA technology to fuse FMRP to a fluorescent protein called Green Fluorescent Protein (GFP). The fluorescent FMRP protein was then introduced into cultured neurons that were isolated from embryonic rat hippocampus, a part of the brain important for learning and memory. Cultured hippocampal neurons provide a powerful tool to enable visualization of FMRP behavior in response to synapse activation. Previous work by Laura Antar and colleagues, in the Bassell laboratory, has shown that activation of a specific metabotropic glutamate receptor (mGluR5) can stimulate the trafficking of FMRP and Fmr1 mRNA granules to dendrites (Antar et. al., Journal of Neuroscience 2003; 24:2648). In more recent work (Antar et al., Genes, Brain and Behavior, 2005), these investigators have further characterized the requirement of microtubules for this dynamic and regulated trafficking, as visualized in living hippocampal neurons using time lapse fluorescent video-microscopy. Collectively, this work (supported by FRAXA) has important implications toward understanding how regulation of mRNA localization and translation by signals important for plasticity, learning and memory may be altered in Fragile X.

P. W. VANDERKLISH & G. M. EDELMAN:
Differential translation and fragile X syndrome

Fragile X syndrome is the most common inherited form of mental retardation. It is caused by the silencing of a single gene, denoted Fmr1, which encodes a protein named after the syndrome, the Fragile X mental retardation protein (FMRP). One of the functions of FMRP is to suppress the synthesis of proteins (translation) from mRNAs that are localized within dendrites, the highly branched protrusion of neurons that receive synaptic input from other neurons. Synapses that use glutamate as a neurotransmitter are characterized in most cases by the presence of a dendritic spine, a small (~1mm) protrusion of the dendritic membrane that makes up the postsynaptic element. The most profound abnormality seen in the brains of Fragile X patients is an overabundance of abnormally long, thin, and tortuous dendritic spines. According to a current theory of Fragile X syndrome, the loss of FMRP leads to an exaggeration of translation that is triggered by a particular subtype of glutamate receptors called group I metabotropic glutamate receptors (mGluRs). Several observations have lead to this theory. First, FMRP is rapidly synthesized at synapses in response to activation of mGluRs, suggesting that it may act as a negative brake on further mRNA translation. Second, translation induced by mGluRs is involved in consolidating a form of long-term depression (LTD) of transmission at glutamatergic synapses. The formation of this long-lasting decrease in synaptic strength, which is itself triggered by mGluRs, is enhanced in mice in that lack FMRP. Third, mGluR-induced translation also leads to an elongation of dendritic spines, such that they resemble the abnormal synaptic phenotypes that are over-represented in Fragile X brain. These observations place Fragile X research at the heart of a long-standing issue in neuroscience. The consolidation of memory and several distinct forms of synaptic plasticity that are thought to provide a neurophysiological basis for memory formation, including LTD, requires mRNA translation and is associated with changes in dendritic spine morphology. A recent convergence of research on Fragile X syndrome and on the involvement of translation in various forms of synaptic plasticity has been very informative on this issue and on mechanisms underlying Fragile X syndrome. Evidence suggests a general relationship in which the receptors that induce distinct forms of efficacy change differentially regulate translation to produce unique spine shapes involved in their consolidation. We discuss several potential mechanisms for differential translation and the notion that Fragile X syndrome represents an exaggeration of one channel in a set of translation-dependent consolidation responses.

D. C. ZARNESCU, G. SHAN, S. T. WARREN, & P. JIN:
Come FLY with us: toward understanding fragile X syndrome

Tiny Fruit Fly Plays BIG Roles - In recent years, fruit fly has been increasingly used to study molecular basis of many human diseases, including the most common form of inherited mental retardation, fragile X syndrome. As a model system, fruit fly bears many advantages for conducting biological research, such as a complete, public available genome sequence, a large collection of flies containing mutations in equivalent genes of the human disease genes, and a very short reproducing-period for performing genetic studies. Initial analysis of fly mutants lacking the fragile X mental retardation protein has revealed that these flies exhibit neuronal and behavioral defects similar to those reported in mouse models as well as in human patients. Therefore, the fly models could provide us powerful tools to further dissect the biological pathways regulated by the fragile X mental retardation protein, and identify potential drugs to clinically treat fragile X syndrome. In this review article, we summarize and discuss the recent progress made in fragile X syndrome study using these fly models.

M. F. BEAR:
Therapeutic implications of the mGluR theory of fragile X mental retardation

Considerable evidence now suggests that the consequences of group 1 metabotropic glutamate receptor (Gp1 mGluR) activation are exaggerated in the absence of the fragile X mental retardation protein, likely reflecting altered dendritic protein synthesis. Abnormal mGluR signaling could be responsible for remarkably diverse psychiatric and neurological symptoms in fragile X syndrome, including delayed cognitive development, seizures, anxiety, movement disorders, and obesity. Thus, drugs that down-regulate signaling by Gp1 mGluRs have great therapeutic potential for treatment of fragile X syndrome.