Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is caused by the loss of function for Fragile X protein (FMRP), an RNA-binding protein thought to regulate synaptic plasticity by controlling the localization and translation of specific mRNAs. We have recently shown that FMRP is required to control the proliferation of the germline in Drosophila. To determine whether FMRP is also required for proliferation during brain development, we examined the distribution of cell cycle markers in dFmr1 brains compared with wild-type throughout larval development. Our results indicate that the loss of dFmr1 leads to a significant increase in the number of mitotic neuroblasts (NB) and BrdU incorporation in the brain, consistent with the notion that FMRP controls proliferation during neurogenesis. Developmental studies suggest that FMRP also inhibits neuroblast exit from quiescence in early larval brains, as indicated by misexpression of Cyclin E. Live imaging experiments indicate that by the third instar larval stage, the length of the cell cycle is unaffected, although more cells are found in S and G2/M in dFmr1 brains compared with wild-type. To determine the role of FMRP in neuroblast division and differentiation, we used Mosaic Analysis with a Repressible Marker (MARCM) approaches in the developing larval brain and found that single dFmr1 NB generate significantly more neurons than controls. Our results demonstrate that FMRP is required during brain development to control the exit from quiescence and proliferative capacity of NB as well as neuron production, which may provide insights into the autistic component of FXS.
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PMID:Fragile X protein controls neural stem cell proliferation in the Drosophila brain. 2050 94

In humans, the absence of Fragile X mental retardation protein (FMRP), an RNA-binding protein, results in Fragile X syndrome, the most common inherited form of intellectual disability. Using biochemical and electrophysiological studies, we found that FMRP binds to the C terminus of the Slack sodium-activated potassium channel to activate the channel in mice. Our findings suggest that Slack activity provides a link between patterns of neuronal firing and changes in protein translation.
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PMID:Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. 2051 34

Fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates synaptic plasticity by repressing translation of specific mRNAs. We found that FMRP binds mRNA encoding the voltage-gated potassium channel Kv3.1b in brainstem synaptosomes. To explore the regulation of Kv3.1b by FMRP, we investigated Kv3.1b immunoreactivity and potassium currents in the auditory brainstem sound localization circuit of male mice. The unique features of this circuit allowed us to control neuronal activity in vivo by exposing animals to high-frequency, amplitude-modulated stimuli, which elicit predictable and stereotyped patterns of input to the anterior ventral cochlear nucleus (AVCN) and medial nucleus of the trapezoid body (MNTB). In wild-type (WT) animals, Kv3.1b is expressed along a tonotopic gradient in the MNTB, with highest levels in neurons at the medial, high-frequency end. At baseline, Fmr1(-/-) mice, which lack FMRP, displayed dramatically flattened tonotopicity in Kv3.1b immunoreactivity and K(+) currents relative to WT controls. Moreover, after 30 min of acoustic stimulation, levels of Kv3.1b immunoreactivity were significantly elevated in both the MNTB and AVCN of WT, but not Fmr1(-/-), mice. These results suggest that FMRP is necessary for maintenance of the gradient in Kv3.1b protein levels across the tonotopic axis of the MNTB, and are consistent with a role for FMRP as a repressor of protein translation. Using numerical simulations, we demonstrate that Kv3.1b tonotopicity may be required for accurate encoding of stimulus features such as modulation rate, and that disruption of this gradient, as occurs in Fmr1(-/-) animals, degrades processing of this information.
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PMID:Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b. 2068 71

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.
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PMID:Toward fulfilling the promise of molecular medicine in fragile X syndrome. 2109 Sep 64

The fragile X mental retardation protein (FMRP) is an RNA-binding protein essential for multiple aspects of neuronal mRNA metabolism. Its absence leads to the fragile X syndrome, the most prevalent genetic form of mental retardation. The anatomical landmark of the disease, also present in the Fmr1 knock-out (KO) mice, is the hyperabundance of immature-looking lengthened dendritic spines. We used the well known continuous production of adult-born granule cells (GCs) in the mouse olfactory bulb (OB) to analyze the consequences of Fmrp loss on the differentiation of GCs. Morphological analysis of GCs in the Fmr1 KO mice showed an increase in spine density without a change in spine length. We developed an RNA interference strategy to cell-autonomously mutate Fmr1 in a wild-type OB network. Mutated GCs displayed an increase in spine density and spine length. Detailed analysis of the spines through immunohistochemistry, electron microscopy, and electrophysiology surprisingly showed that, despite these abnormalities, spines receive normal glutamatergic synapses, and thus that mutated adult-born neurons are synaptically integrated into the OB circuitry. Time-course analysis of the spine defects showed that Fmrp cell-autonomously downregulates the level and rate of spine production and limits their overgrowth. Finally, we report that Fmrp does not regulate dendritogenesis in standard conditions but is necessary for activity-dependent dendritic remodeling. Overall, our study of Fmrp in the context of adult neurogenesis has enabled us to carry out a precise dissection of the role of Fmrp in neuronal differentiation and underscores its pleiotropic involvement in both spinogenesis and dendritogenesis.
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PMID:Fragile X mental retardation protein regulates new neuron differentiation in the adult olfactory bulb. 2130 57

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is caused by the loss of function for Fragile X Mental Retardation Protein (FMRP), a selective RNA-binding protein with a demonstrated role in the localized translation of target mRNAs at synapses. Several recent studies provide compelling evidence for a new role of FMRP in the development of the nervous system, during neurogenesis. Using a multi-faceted approach and a variety of model systems ranging from cultured neurospheres and progenitor cells to in vivo Drosophila and mouse models these reports indicate that FMRP is required for neural stem and progenitor cell proliferation, differentiation, survival, as well as regulation of gene expression. Here we compare and contrast these recent reports and discuss the implications of FMRP's new role in embryonic and adult neurogenesis, including the development of novel therapeutic approaches to FXS and related neurological disorders such as autism.
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PMID:Heads-up: new roles for the fragile X mental retardation protein in neural stem and progenitor cells. 2140 21

Rac1, a protein of the Rho GTPase subfamily, has been implicated in neuronal and spine development as well as the formation of synapses with appropriate partners. Dendrite and spine abnormalities have been implicated in several psychiatric disorders such as Fragile X syndrome, where neurons show a high density of long, thin, and immature dendritic spines. Although abnormalities in dendrites and spines have been correlated with impaired cognitive abilities in mental retardation, the causes of these malformations are not yet well understood. Fragile X syndrome is the most common type of inherited mental retardation caused by the absence of FMRP protein, a RNA-binding protein implicated in the regulation of mRNA translation and transport, leading to protein synthesis. We suggest that FMRP might act as a negative regulator on the synthesis of Rac1. Maintaining an optimal level of Rac1 and facilitating the reorganization of the cytoskeleton likely leads to normal neuronal morphology during activity-dependent plasticity. In our study, we first demonstrated that Rac1 is not only associated but necessary for normal spine development and long-term synaptic plasticity. We further showed that, in Fmr1 knockout mice, lack of FMRP induces an overactivation of Rac1 in the mouse brain and other organs that have been shown to be altered in Fragile X syndrome. In those animals, pharmacological manipulation of Rac1 partially reverses their altered long-term plasticity. Thus, regulation of Rac1 may provide a functional link among deficient neuronal morphology, aberrant synaptic plasticity and cognition impairment in Fragile X syndrome.
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PMID:Modulation of dendritic spines and synaptic function by Rac1: a possible link to Fragile X syndrome pathology. 2164 77

Fragile X syndrome (FXS) is the first cause of inherited intellectual disability, due to the silencing of the X-linked Fragile X Mental Retardation 1 gene encoding the RNA-binding protein FMRP. While extensive studies have focused on the cellular and molecular basis of FXS, neither human Fragile X patients nor the mouse model of FXS--the Fmr1-null mouse--have been profiled systematically at the metabolic and neurochemical level to provide a complementary perspective on the current, yet scattered, knowledge of FXS. Using proton high-resolution magic angle spinning nuclear magnetic resonance ((1)H HR-MAS NMR)-based metabolic profiling, we have identified a metabolic signature and biomarkers associated with FXS in various brain regions of Fmr1-deficient mice. Our study highlights for the first time that Fmr1 gene inactivation has profound, albeit coordinated consequences in brain metabolism leading to alterations in: (1) neurotransmitter levels, (2) osmoregulation, (3) energy metabolism, and (4) oxidative stress response. To functionally connect Fmr1-deficiency to its metabolic biomarkers, we derived a functional interaction network based on the existing knowledge (literature and databases) and show that the FXS metabolic response is initiated by distinct mRNA targets and proteins interacting with FMRP, and then relayed by numerous regulatory proteins. This novel "integrated metabolome and interactome mapping" (iMIM) approach advantageously unifies novel metabolic findings with previously unrelated knowledge and highlights the contribution of novel cellular pathways to the pathophysiology of FXS. These metabolomic and integrative systems biology strategies will contribute to the development of potential drug targets and novel therapeutic interventions, which will eventually benefit FXS patients.
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PMID:A metabolomic and systems biology perspective on the brain of the fragile X syndrome mouse model. 2190 Mar 87

Stem cells, which can self-renew and produce different cell types, are regulated by both extrinsic signals and intrinsic factors. Fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by the functional loss of fragile X mental retardation protein (FMRP). FMRP is a selective RNA-binding protein that forms a messenger ribonucleoprotein (mRNP) complex that associates with polyribosomes. Recently, the role of Fmrp in stem cell biology has been explored in both Drosophila and the mouse. In this chapter, we discuss the role of FMRP in regulating the proliferation and differentiation of stem cells.
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PMID:Fragile X mental retardation protein and stem cells. 2200 51

Fragile X syndrome, the most prevalent inheritable mental retardation, is caused by the loss of fragile X mental retardation protein (FMRP) expression. FMRP is an RNA-binding protein with nucleo-cytoplasmic shuttle activity, proposed to act as a translation regulator of specific mRNAs in the brain. It has been shown that FMRP uses its arginine-glycine-glycine (RGG) box domain to bind a subset of mRNA targets that form a G-quadruplex structure. FMRP has also been shown to undergo the post-translational modifications of arginine methylation and phosphorylation, as well as alternative splicing, resulting in multiple isoforms. The alternative splice isoforms investigated in this study, isoform 1 (ISO1), isoform 2 (ISO2), and isoform 3 (ISO3), are created by the alternative splicing acceptor site at exon 15. FMRP ISO2 and ISO3 are truncated by 12 and 13 residues, respectively, relative to the longest FMRP isoform ISO1. These truncations, which are in the close proximity of the RGG box domain, preserve the integrity of the RGG box in all three isoforms, but eliminate the in vivo phosphorylation sites, present only on FMRP ISO1. We have expressed and purified recombinant FMRP ISO1, ISO2 and ISO3 in Escherichia coli, free of post-translational modifications, and by using fluorescence spectroscopy, we show that each FMRP isoform binds G-quadruplex RNA, albeit with different binding affinities, suggesting that naturally occurring sequence modifications in the proximity of the RGG box modulate its G-quadruplex RNA binding ability.
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PMID:Analysis of the Fragile X mental retardation protein isoforms 1, 2 and 3 interactions with the G-quadruplex forming semaphorin 3F mRNA. 2213 4


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