Function of FMRP domains in regulating distinct roles of neuronal protein synthesis

The Fragile X Mental Retardation Protein (FMRP) is an RNA Binding Protein that regulates translation of mRNAs, essential for synaptic development and plasticity. FMRP interacts with a specific set of mRNAs and aids in their microtubule dependent transport and regulates their translation through its association with ribosomes. However, the biochemical role of individual domains of FMRP in forming neuronal granules and associating with microtubules and ribosomes is currently undefined. Here, we report that the C-terminus domain of FMRP is sufficient to bind to ribosomes as well as polysomes akin to the full-length protein. Furthermore, the C-terminus domain alone is essential and responsible for FMRP-mediated translation repression in neurons. However, FMRP-mediated puncta formation and microtubule association is favored by the synergistic combination of FMRP domains and not by individual domains. Interestingly, we show that the phosphorylation of hFMRP at Serine-500 is important in modulating the dynamics of translation by controlling ribosome/polysome association. This is a fundamental mechanism governing the size and number of FMRP puncta, which appear to contain actively translating ribosomes. Finally through the use of pathogenic mutations, we emphasize the hierarchy of the domains of FMRP in their contribution to translation regulation.

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Cells Lacking the Fragile X Mental Retardation Protein (FMRP) have Normal RISC Activity but Exhibit Altered Stress Granule Assembly

Molecular Biology of the Cell ◽

10.1091/mbc.e08-07-0737 ◽

2009 ◽

Vol 20 (1) ◽

pp. 428-437 ◽

Cited By ~ 53

Author(s):

Marie-Cécile Didiot ◽

Murugan Subramanian ◽

Eric Flatter ◽

Jean-Louis Mandel ◽

Hervé Moine

Keyword(s):

Mental Retardation ◽

Molecular Mechanisms ◽

Rna Binding ◽

Fragile X ◽

Stress Granule ◽

Translation Regulation ◽

Positive Role ◽

Granule Formation ◽

Fragile X Mental Retardation ◽

Mental Retardation Protein

The fragile X mental retardation protein (FMRP) is an RNA-binding protein involved in the mRNA metabolism. The absence of FMRP in neurons leads to alterations of the synaptic plasticity, probably as a result of translation regulation defects. The exact molecular mechanisms by which FMRP plays a role in translation regulation have remained elusive. The finding of an interaction between FMRP and the RNA interference silencing complex (RISC), a master of translation regulation, has suggested that both regulators could be functionally linked. We investigated here this link, and we show that FMRP exhibits little overlap both physically and functionally with the RISC machinery, excluding a direct impact of FMRP on RISC function. Our data indicate that FMRP and RISC are associated to distinct pools of mRNAs. FMRP, unlike RISC machinery, associates with the pool of mRNAs that eventually goes into stress granules upon cellular stress. Furthermore, we show that FMRP plays a positive role in this process as the lack of FMRP or a point mutant causing a severe fragile X alter stress granule formation. Our data support the proposal that FMRP plays a role in controlling the fate of mRNAs after translation arrest.

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A novel role of fragile X mental retardation protein in pre-mRNA alternative splicing through RNA-binding protein 14

Neuroscience ◽

10.1016/j.neuroscience.2017.02.044 ◽

2017 ◽

Vol 349 ◽

pp. 64-75 ◽

Cited By ~ 19

Author(s):

Lin-Tao Zhou ◽

Shun-Hua Ye ◽

Hai-Xuan Yang ◽

Yong-Ting Zhou ◽

Qi-Hua Zhao ◽

...

Keyword(s):

Mental Retardation ◽

Alternative Splicing ◽

Rna Binding ◽

Fragile X ◽

Binding Protein ◽

Rna Binding Protein ◽

Fragile X Mental Retardation ◽

Mental Retardation Protein

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Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome

Cerebral Cortex ◽

10.1093/cercor/bhy192 ◽

2018 ◽

Vol 29 (8) ◽

pp. 3241-3252 ◽

Cited By ~ 12

Author(s):

Thomas Maurin ◽

Francesca Melancia ◽

Marielle Jarjat ◽

Liliana Castro ◽

Lara Costa ◽

...

Keyword(s):

Fragile X Syndrome ◽

Translational Regulation ◽

Rna Binding ◽

Fragile X ◽

The Social ◽

Mental Retardation Protein ◽

Camp And Cgmp ◽

The Brain

Abstract The fragile X mental retardation protein (FMRP) is an RNA-binding protein involved in translational regulation of mRNAs that play key roles in synaptic morphology and plasticity. The functional absence of FMRP causes the fragile X syndrome (FXS), the most common form of inherited intellectual disability and the most common monogenic cause of autism. No effective treatment is available for FXS. We recently identified the Phosphodiesterase 2A (Pde2a) mRNA as a prominent target of FMRP. PDE2A enzymatic activity is increased in the brain of Fmr1-KO mice, a recognized model of FXS, leading to decreased levels of cAMP and cGMP. Here, we pharmacologically inhibited PDE2A in Fmr1-KO mice and observed a rescue both of the maturity of dendritic spines and of the exaggerated hippocampal mGluR-dependent long-term depression. Remarkably, PDE2A blockade rescued the social and communicative deficits of both mouse and rat Fmr1-KO animals. Importantly, chronic inhibition of PDE2A in newborn Fmr1-KO mice followed by a washout interval, resulted in the rescue of the altered social behavior observed in adolescent mice. Altogether, these results reveal the key role of PDE2A in the physiopathology of FXS and suggest that its pharmacological inhibition represents a novel therapeutic approach for FXS.

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RNA-Binding Specificity of the Human Fragile X Mental Retardation Protein

Journal of Molecular Biology ◽

10.1016/j.jmb.2020.04.021 ◽

2020 ◽

Vol 432 (13) ◽

pp. 3851-3868 ◽

Cited By ~ 4

Author(s):

Youssi M. Athar ◽

Simpson Joseph

Keyword(s):

Mental Retardation ◽

Rna Binding ◽

Fragile X ◽

Binding Specificity ◽

Fragile X Mental Retardation ◽

Mental Retardation Protein

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Why is vision impaired in fragile X premutation carriers? The role of fragile X mental retardation protein and potential FMR1 mRNA toxicity

Neuroscience ◽

10.1016/j.neuroscience.2012.01.005 ◽

2012 ◽

Vol 206 ◽

pp. 183-189 ◽

Cited By ~ 13

Author(s):

S. Kéri ◽

G. Benedek

Keyword(s):

Mental Retardation ◽

Fragile X ◽

Fragile X Mental Retardation ◽

Fragile X Premutation ◽

Mental Retardation Protein ◽

Fmr1 Mrna

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The RNA-binding fragile-X mental retardation protein and its role beyond the brain

Biophysical Reviews ◽

10.1007/s12551-020-00730-4 ◽

2020 ◽

Vol 12 (4) ◽

pp. 903-916 ◽

Cited By ~ 1

Author(s):

Cassandra Malecki ◽

Brett D. Hambly ◽

Richmond W. Jeremy ◽

Elizabeth N. Robertson

Keyword(s):

Mental Retardation ◽

Rna Binding ◽

Fragile X ◽

Fragile X Mental Retardation ◽

Mental Retardation Protein ◽

The Brain

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Role of microRNA Pathway in Mental Retardation

The Scientific World JOURNAL ◽

10.1100/tsw.2007.208 ◽

2007 ◽

Vol 7 ◽

pp. 146-154 ◽

Cited By ~ 12

Author(s):

Abrar Qurashi ◽

Shuang Chang ◽

Peng Jin

Keyword(s):

Mental Retardation ◽

Fragile X Syndrome ◽

Genetic Basis ◽

Fragile X ◽

Biological Pathways ◽

Fragile X Mental Retardation ◽

Mental Retardation Protein ◽

Mirna Pathway ◽

Microrna Pathway

Deficits in cognitive functions lead to mental retardation (MR). Understanding the genetic basis of inherited MR has provided insights into the pathogenesis of MR. Fragile X syndrome is one of the most common forms of inherited MR, caused by the loss of functional Fragile X Mental Retardation Protein (FMRP).MicroRNAs (miRNAs) are endogenous, single-stranded RNAs between 18 and 25 nucleotides in length, which have been implicated in diversified biological pathways. Recent studies have linked the miRNA pathway to fragile X syndrome. Here we review the role of the miRNA pathway in fragile X syndrome and discuss its implication in MR in general.

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Kinase pathway inhibition restores PSD95 induction in neurons lacking fragile X mental retardation protein

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812056116 ◽

2019 ◽

pp. 201812056

Author(s):

Ying Yang ◽

Yang Geng ◽

Dongyun Jiang ◽

Lin Ning ◽

Hyung Joon Kim ◽

...

Keyword(s):

Protein Synthesis ◽

Mental Retardation ◽

Rna Binding ◽

Fragile X ◽

Alternative Pathways ◽

Fragile X Mental Retardation ◽

Mrna Targets ◽

Mental Retardation Protein ◽

Pathway Inhibition

Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates translation of numerous mRNA targets, some of which are present at synapses. While protein synthesis deficits have long been postulated as an etiology of FXS, how FMRP loss affects distributions of newly synthesized proteins is unknown. Here we investigated the role of FMRP in regulating expression of new copies of the synaptic protein PSD95 in an in vitro model of synaptic plasticity. We find that local BDNF application promotes persistent accumulation of new PSD95 at stimulated synapses and dendrites of cultured neurons, and that this accumulation is absent in FMRP-deficient mouse neurons. New PSD95 accumulation at sites of BDNF stimulation does not require known mechanisms regulating FMRP–mRNA interactions but instead requires the PI3K-mTORC1-S6K1 pathway. Surprisingly, in FMRP-deficient neurons, BDNF induction of new PSD95 accumulation can be restored by mTORC1-S6K1 blockade, suggesting that constitutively high mTORC1-S6K1 activity occludes PSD95 regulation by BDNF and that alternative pathways exist to mediate induction when mTORC1-S6K1 is inhibited. This study provides direct evidence for deficits in local protein synthesis and accumulation of newly synthesized protein in response to local stimulation in FXS, and supports mTORC1-S6K1 pathway inhibition as a potential therapeutic approach for FXS.

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