Fragile X Mental Retardation Protein Regulates Translation by Binding Directly to the Ribosome

Chen, Eileen; Sharma, Manjuli R.; Shi, Xueyan; Agrawal, Rajendra K.; Joseph, Simpson

doi:10.1016/j.molcel.2014.03.023

Cited by 230 publications

(255 citation statements)

References 78 publications

Supporting

Mentioning

239

Contrasting

Unclassified

Order By: Relevance

“…Consistent with this role are numerous reports of excess mRNA translation and protein synthesis in animal models of FXS and cells from humans with FXS [61][62][63][64][65][66]. Recent studies suggest that FMRP-mediated repression involves its association with polyribosomes and ribosome stalling or direct interaction with the 80S ribosomal subunit [39,67,68]. Regardless of whether FMRP acts to stall ribosomes by binding indiscriminately along coding sequences [67] or directly to the ribosome [68], these models are unlikely to explain how FMRP selectively binds only 4 % of mRNA in brain [69].…”

Section: Mechanisms Of Fmrp-mediated Regulation Of Mrna Translation Imentioning

confidence: 66%

“…Recent studies suggest that FMRP-mediated repression involves its association with polyribosomes and ribosome stalling or direct interaction with the 80S ribosomal subunit [39,67,68]. Regardless of whether FMRP acts to stall ribosomes by binding indiscriminately along coding sequences [67] or directly to the ribosome [68], these models are unlikely to explain how FMRP selectively binds only 4 % of mRNA in brain [69]. The search for cis-elements is an important direction to pursue, and the role of short sequence motifs in FMRP targets has been reported.…”

Section: Mechanisms Of Fmrp-mediated Regulation Of Mrna Translation Imentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

View full text Add to dashboard Cite

Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

show abstract

Section: Mechanisms Of Fmrp-mediated Regulation Of Mrna Translation Imentioning

confidence: 66%

Section: Mechanisms Of Fmrp-mediated Regulation Of Mrna Translation Imentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Notably, binding of FMRP to G-rich RNAs in vitro requires only the RGG motif, which specifically interacts with natural and in vitro selected G-quadruplex-containing RNAs such as a 35-nucleotide sc1 RNA (21,(26)(27)(28)(29). Recent studies showed that G-quadruplexes facilitate mRNA interactions with ribosome-bound FMRP (30), whereas the RGG motif, in addition to mRNA binding, contributes to association with ribosomes and proteins and translational control (14,(31)(32)(33)(34). The RGG motif is well conserved in FMRP of vertebrates but differs significantly from…”

mentioning

confidence: 99%

Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP

Vasilyev

Polonskaia

Darnell

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

180

181

View full text Add to dashboard Cite

Fragile X Mental Retardation Protein (FMRP) is a regulatory RNA binding protein that plays a central role in the development of several human disorders including Fragile X Syndrome (FXS) and autism. FMRP uses an arginine-glycine-rich (RGG) motif for specific interactions with guanine (G)-quadruplexes, mRNA elements implicated in the disease-associated regulation of specific mRNAs. Here we report the 2.8-Å crystal structure of the complex between the human FMRP RGG peptide bound to the in vitro selected G-rich RNA. In this model system, the RNA adopts an intramolecular K + -stabilized G-quadruplex structure composed of three G-quartets and a mixed tetrad connected to an RNA duplex. The RGG peptide specifically binds to the duplex-quadruplex junction, the mixed tetrad, and the duplex region of the RNA through shape complementarity, cation-π interactions, and multiple hydrogen bonds. Many of these interactions critically depend on a type I β-turn, a secondary structure element whose formation was not previously recognized in the RGG motif of FMRP. RNA mutagenesis and footprinting experiments indicate that interactions of the peptide with the duplex-quadruplex junction and the duplex of RNA are equally important for affinity and specificity of the RGG-RNA complex formation. These results suggest that specific binding of cellular RNAs by FMRP may involve hydrogen bonding with RNA duplexes and that RNA duplex recognition can be a characteristic RNA binding feature for RGG motifs in other proteins.R NA-binding proteins (RBPs) control all aspects of RNA metabolism and are fundamental to core cellular processes. ∼14% of identified human RBPs are implicated in a broad spectrum of human pathologies, including neurodegenerative and muscular diseases, metabolic disorders, and cancers (1, 2). Fragile X Mental Retardation Protein (FMRP) is among the most important RBPs because of its central role in several human diseases (3). Loss of FMRP function due to CGG triplet repeat expansion-associated transcriptional silencing or missense mutations in the protein (4, 5) lead to fragile X syndrome (FXS), the most common cause of inherited intellectual disability. Mutations in FMRP are also the leading monogenic cause of autism (6, 7). Intermediate length repeat expansions in the FMR1 gene are linked to fragile X-associated tremor ataxia syndrome (8) and fragile X-associated primary ovarian insufficiency (9).FMRP contains four canonical nucleic acid-binding motifs, three KH domains and one arginine-glycine-rich (RGG) box, which mediate interactions with RNAs in mRNA transport, storage, stability, and regulation of translation (Fig. 1A) (3, 10). Each KH domain has been reported to have a mutation either causing FXS or found in patients with intellectual disability (4, 5, 11). In neurons, FMRP associates with a subset of mRNAs and represses their translation both in the cell body and near synapses (12). Loss of repression of these mRNAs is associated with alterations in synaptic plasticity and dendritic spine dynamics thought to underlie...

show abstract

“…The lack of obvious overlap between several of these candidate lists calls into question the RNA binding specificity of FMRP (13). How FMRP controls the translation of hundreds of distinct proteins, whether by direct mRNA binding or in an mRNA-independent manner [e.g., through its direct binding with the ribosome (14)], is still unclear. With these hundreds of potential target mRNAs, another key question still awaits an answer: Are there specific mRNAs whose deregulation matters the most for the pathology?…”

mentioning

confidence: 99%

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Tabet

Moutin

Becker

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

View full text Add to dashboard Cite

Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine.F ragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, is due to the transcriptional inactivation of the Fragile X Mental Retardation 1 gene (FMR1) (1, 2). The FMR1 knockout (KO) mouse (Fmr1 −/y ) replicates phenotypes similar to human symptoms-including autistic-like behaviors, cognitive deficits, and hyperactivity-as well as abnormal dendritic spine morphology (3). FMR1 encodes Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein associated to polyribosomes and involved in the translational control of mRNAs important for synaptic plasticity (4). Consistent with a posttranscriptional function, the absence of FMRP in Fmr1 −/y mouse causes abnormal signaling of group 1 metabotropic glutamate receptors (mGluRI), leading to several forms of abnormal synaptic plasticity that rely on protein translation (5, 6). Protein expression analyses confirmed a role of FMRP in neuronal translational control (7), but the extent of this control remains unclear. Although several studies focusing on individual mRNA targets (e.g., Fmr1, Map1b, Psd95, App, etc.) suggest specific control by FMRP (2), studies of global translation, including in vivo labeling in the Fmr1 −/y mouse (8), showed thousands of neuronal proteins deregulated in the absence of FMRP, pointing toward a general translational derepression. Studies seeking to identify the transcripts controlled by FMRP identified can...

show abstract

Fragile X Mental Retardation Protein Regulates Translation by Binding Directly to the Ribosome

Cited by 230 publications

References 78 publications

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Contact Info

Product

Resources

About