Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0025362 (mental retardation)
15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Fragile X mental retardation-1 (Fmr1) gene encodes a multifunctional protein, FMRP, with intrinsic RNA binding activity. We have developed an approach, antibody-positioned RNA amplification (APRA), to identify the RNA cargoes associated with the in vivo configured FMRP messenger ribonucleoprotein (mRNP) complex. Using APRA as a primary screen, putative FMRP RNA cargoes were assayed for their ability to bind directly to FMRP using traditional methods of assessing RNA-protein interactions, including UV-crosslinking and filter binding assays. Approximately 60% of the APRA-defined mRNAs directly associate with FMRP. By examining a subset of these mRNAs and their encoded proteins in brain tissue from Fmr1 knockout mice, we have observed that some of these cargoes as well as the proteins they encode show discrete changes in abundance and/or differential subcellular distribution. These data are consistent with spatially selective regulation of multiple biological pathways by FMRP.
...
PMID:RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. 1257 50

Fragile X syndrome - a common form of inherited mental retardation - is caused by the loss of the fragile X mental retardation 1 protein (FMRP). FMRP is an RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with translating polyribosomes. It has been proposed that FMRP is involved in synaptic plasticity through the regulation of mRNA transportation and translation. Recent advances in the identification of the mRNA ligands that are bound by FMRP, the RNA sequence and structure required for FMRP-RNA interaction, and the physiological consequences of FMRP deficiency in the brain are important steps towards understanding the molecular pathogenesis of fragile X syndrome, and learning and memory in general.
...
PMID:New insights into fragile X syndrome: from molecules to neurobehaviors. 1263 95

The loss of the fragile X mental retardation protein (FMRP) is responsible for the most common cause of inherited mental retardation called the fragile X syndrome. FMRP is suspected to participate in the synaptic plasticity of neurons by acting on posttranscriptional control of gene expression. FMRP is an RNA binding protein that associates with mRNAs together with other proteins to form large ribonucleoprotein complexes. These complexes are proposed to participate in the transport, localization and translation of target mRNAs. Progress has been made recently in the identification of the mRNAs and the proteins present in these complexes and a possible connection with the micro-RNA dependent regulatory pathway has been established.
...
PMID:The RNA binding protein FMRP: new connections and missing links. 1286 85

Mental retardation is a frequent cause of intellectual and physical impairment. Several genes associated with mental retardation have been mapped to the X chromosome, among them, there is FMR1. The absence of or mutation in the Fragile Mental Retardation Protein, FMRP, is responsible for the Fragile X syndrome. FMRP is an RNA binding protein that shuttles between the nucleus and the cytoplasm. FMRP binds to several mRNAs including its own mRNA at a sequence region containing a G quartet structure. Some of the candidate downstream genes recently identified encode for synaptic proteins. Neuronal studies indicate that FMRP is located at synapses and loss of FMRP affects synaptic plasticity. At the synapses, FMRP acts as a translational repressor and in particular regulates translation of specific dendritic mRNAs, some of which encode cytoskeletal proteins and signal transduction molecules. This action occurs via a ribonucleoprotein complex that includes a small dendritic non-coding neuronal RNA that determines the specificity of FMRP function via a novel mechanism of translational repression. Since local protein synthesis is required for synaptic development and function, this role of FMRP likely underlies some of the behavioural and developmental symptoms of FRAXA patients. Finally we review recent work on the Drosophila system that connects cytoskeleton remodelling and FMRP function.
...
PMID:Molecular insights into mental retardation: multiple functions for the Fragile X mental retardation protein? 1511 19

Transport and translation of mRNA are tightly coupled to ensure strict temporal and spatial expression of nascent proteins. Fragile X mental retardation protein (FMRP) has been shown to be involved in translational regulation and is found in ribonucleoprotein (RNP) granules that travel along dendrites of neurons. In this study, GFP-tagged Drosophila homologue of FMRP (dFMR) was used to visualize RNP granule movement in Drosophila S2 cells. GFP-dFMR form granules that contain both endogenous dFMR and mRNA. Live fluorescence microscopy revealed that dFMR-containing RNP granules move bidirectionally in thin processes formed by S2 cells in the presence of cytochalasin D. Knocking down the heavy chains of either kinesin-1 (kinesin heavy chain) or cytoplasmic dynein (dynein heavy chain) by RNA interference blocks the movement of the dFMR granules. In contrast, knockdown of kinesin light chain (KLC), which is typically necessary for movement of membrane organelles by kinesin-1, had no effect on the dFMR granule translocation. In immunoprecipitation assays, dFMR associates with both kinesin heavy chain and dynein heavy chain, but not KLC. Based on these findings, we conclude that dFMR-containing RNP granules are moved by both kinesin-1 and cytoplasmic dynein and that KLC is not essential and is likely missing from RNP-transporting kinesin-1.
...
PMID:Transport of Drosophila fragile X mental retardation protein-containing ribonucleoprotein granules by kinesin-1 and cytoplasmic dynein. 1558 37

Translational regulation of maternal mRNAs in distinct temporal and spatial patterns underlies many key decisions in developing eggs and embryos. In Drosophila, Orb is responsible for mediating the translational activation of mRNAs localized within the developing oocyte. Orb is a germline-specific RNA binding protein and is one of the founding members of the CPEB family of translational regulators. Here we show that Orb associates with the Drosophila Fragile X Mental Retardation (dFMR1) protein as part of a ribonucleoprotein complex that controls the localized translation of mRNAs in developing egg chambers. One of the key orb regulatory targets is orb mRNA, and this autoregulatory activity is critical for ensuring that Orb protein is expressed at high levels in the oocyte. We show that dFMR1 functions as a negative regulator in the orb autoregulatory circuit, downregulating orb mRNA translation.
...
PMID:The Drosophila fragile X protein functions as a negative regulator in the orb autoregulatory pathway. 1573 29

Fragile X syndrome (FXS) is the most frequent cause of inherited mental retardation and is largely caused by a loss of expression of fragile X mental retardation protein (FMRP), encoded by fragile X retardation gene-1 (Fmr1). FMRP is a multifunction protein, with intrinsic RNA-binding properties, which is a component of ribonucleoprotein complex associated with polyribosomes. The properties of FMRP indicate that it might participate in post-transcriptional processes in the regulation of some mRNA species, including localization, stability and translational control. However, the function of FMRP related to the pathologenesis in FXS is largely unknown. Many efforts were undertaken to identify the putative specific RNA targets as well as the FMRP-related proteins and to identify the effect of FMRP absence on the corresponding proteins. Here we present our efforts using proteomics approach to explore the differential expression profiling of mouse cerebella immortal cell, in which we changed the expression of FMRP by expressing Fmr1 gene with nuclear export signal (NES) mutation. This mutation makes FMRP unable to shuttle from nucleus to cytoplasm and leads to nuclear instead of cytoplasmic location as usual, which was hypothesized to affect the pathways of groups of RNAs or proteins related with FMRP. In present study, 56 proteins were found to be differentially expressed in transfected R2 neuronal cells, including 16 decreased expressions and 40 increased expressions. The differentially expressed proteins play roles in diverse physiological processes, such as neuronal plasticity, spermatogenesis and craniofacial and limb development etc. In addition, the expressions of three mRNA identified as FMRP targets in fragile X cell were tested in present model cells. All these results provide new insights to the role of FMRP in the disease.
...
PMID:Expression of fragile X mental retardation-1 gene with nuclear export signal mutation changes the expression profiling of mouse cerebella immortal neuronal cell. 1613 Jan 71

Fragile X mental retardation 1 protein (FMRP) is an RNA-binding protein whose absence results in the fragile X syndrome, the most common inherited form of mental retardation. FMRP contains multiple domains with apparently differential affinity to mRNA and interacts also with protein partners present in ribonucleoprotein complexes called RNA granules. In neurons, these particles travel along dendrites and axons to translocate mRNAs to specific destinations in spines and growth cones, where local synthesis of neuro-specific proteins is taking place. However, the molecular mechanisms of how RNA granules are translocated to dendrites remained unknown. We report here the identification and characterization of the motor protein KIF3C as a novel FMRP-interacting protein. In addition, using time-lapse videomicroscopy, we studied the dynamics and kinetics of FMRP-containing RNA granules in dendrites and show that a KIF3C dominant-negative impedes their distal transport. We therefore propose that, in addition to modulate the translation of its mRNA targets, FMRP acts also as a molecular adaptor between RNA granules and the neurospecific kinesin KIF3C that powers their transport along neuronal microtubules.
...
PMID:The fragile X mental retardation protein is a molecular adaptor between the neurospecific KIF3C kinesin and dendritic RNA granules. 1788 55

All-trans-retinoic acid stimulates dendritic growth in hippocampal neurons within minutes by activating mitogen-activated protein kinase and mTOR and increasing dendritic translation of calcium calmodulin-dependent protein kinase II alpha and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate receptor subunit GluR1. Hippocampal neurons express RARalpha in dendrites, and knocking down RARalpha prevents all-trans-retinoic acid effects on dendritic growth. Here we show, by liquid chromatography/mass spectrometry analysis of immunoaffinity isolates of hippocampal neurons, that RARalpha partners with many RNA-binding proteins and translation factors conveyed in dendritic RNA transport granules, including the purine-rich element-binding protein, Pur alpha. The interaction of RARalpha with Pur alpha, an RNA-binding protein required for dendritic RNA transport, and other RNA-binding proteins was confirmed by tandem affinity purification. Confocal microscopy confirmed localization of neuronal RARalpha in dendritic RNA granules with Pur alpha and FMRP (the fragile x mental retardation protein). Hippocampal RARalpha also associates with mRNA, e.g. encoding GluR1 and calcium calmodulin-dependent protein kinase II alpha. Consistent with a granule function of conveying translationally silenced mRNA, RARalpha inhibits translation initiation, independent of 7-methylguanylate cap or poly(A) tail, and prompts mRNA redistribution to silencing ribonucleoprotein particles. These data afford a mechanism for rapid stimulation of dendritic growth by all-trans-retinoic acid and reveal that the ligand-dependent transcription factor RARalpha also regulates translation.
...
PMID:The nuclear transcription factor RARalpha associates with neuronal RNA granules and suppresses translation. 1849 61

Lack of fragile X mental retardation protein (FMRP) causes Fragile X Syndrome, the most common form of inherited mental retardation. FMRP is an RNA-binding protein and is a component of messenger ribonucleoprotein complexes, associated with brain polyribosomes, including dendritic polysomes. FMRP is therefore thought to be involved in translational control of specific mRNAs at synaptic sites. In mice lacking FMRP, protein synthesis-dependent synaptic plasticity is altered and structural malformations of dendritic protrusions occur. One hypothesized cause of the disease mechanism is based on exaggerated group I mGluR receptor activation. In this study, we examined the effect of the mGluR5 antagonist MPEP on Fragile X related behavior in Fmr1 KO mice. Our results demonstrate a clear defect in prepulse inhibition of startle in Fmr1 KO mice, that could be rescued by MPEP. Moreover, we show for the first time a structural rescue of Fragile X related protrusion morphology with two independent mGluR5 antagonists.
...
PMID:Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. 1857 Oct 98


<< Previous 1 2 3 Next >>

---