scholarly journals Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome

Gene Therapy ◽  
2009 ◽  
Vol 16 (9) ◽  
pp. 1122-1129 ◽  
Author(s):  
Z Zeier ◽  
A Kumar ◽  
K Bodhinathan ◽  
J A Feller ◽  
T C Foster ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Mouse Model ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Synaptic Function ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein

scholarly journals Role of microRNA Pathway in Mental Retardation

2007 ◽  
Vol 7 ◽  
pp. 146-154 ◽  
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.

scholarly journals The Fragile X Mental Retardation Protein: A Valuable Partner in the Battle against Epileptogenesis

2009 ◽  
Vol 9 (4) ◽  
pp. 116-118 ◽  
Author(s):  
Lisa R. Merlin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Metabotropic Glutamate Receptor ◽  
Mossy Fiber ◽  
Fragile X ◽  
Critical Role ◽  
Fmr1 Gene ◽  
Metabotropic Glutamate ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein

Correction of Fragile X Syndrome in Mice. Dölen G, Osterweil E, Rao BSS, Smith GB, Auerbach BD, Chattarji S, Bear MF. Neuron 2007;56:955–962. Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders. Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome. Qiu LF, Lu TJ, Hu XL, Yi YH, Liao WP, Xiong ZQ. Cereb Cortex 2009 in press. (doi:10.1093/cercor/bhn163) Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20–25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically accelerated in Fmr1 KO mice, and Fmr1 KO mice also displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after kindling. The accelerated rate of kindling was partially repressed by inhibiting N-methyl-D-aspartic acid receptor (NMDAR) with MK-801 or mGluR5 receptor with 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The rate of kindling development in WT was not effected by MPEP, however, suggesting that FMRP normally suppresses epileptogenic signaling downstream of metabotropic glutamate receptors. Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation.

scholarly journals Dynamic Association of the Fragile X Mental Retardation Protein as a Messenger Ribonucleoprotein between Microtubules and Polyribosomes

2008 ◽  
Vol 19 (1) ◽  
pp. 105-114 ◽  
Author(s):  
Houping Wang ◽  
Jason B. Dictenberg ◽  
Li Ku ◽  
Wen Li ◽  
Gary J. Bassell ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Translational Regulation ◽  
Rna Binding ◽  
Fragile X ◽  
Synaptic Function ◽  
Dependent Manner ◽  
Fragile X Mental Retardation ◽  
Messenger Ribonucleoprotein ◽  
Mental Retardation Protein ◽  
Neuronal Processes

The fragile X mental retardation protein (FMRP) is a selective RNA-binding protein that regulates translation and plays essential roles in synaptic function. FMRP is bound to specific mRNA ligands, actively transported into neuronal processes in a microtubule-dependent manner, and associated with polyribosomes engaged in translation elongation. However, the biochemical relationship between FMRP–microtubule association and FMRP–polyribosome association remains elusive. Here, we report that although the majority of FMRP is incorporated into elongating polyribosomes in the soluble cytoplasm, microtubule-associated FMRP is predominantly retained in translationally dormant, polyribosome-free messenger ribonucleoprotein (mRNP) complexes. Interestingly, FMRP–microtubule association is increased when mRNPs are dynamically released from polyribosomes as a result of inhibiting translation initiation. Furthermore, the I304N mutant FMRP that fails to be incorporated into polyribosomes is associated with microtubules in mRNP particles and transported into neuronal dendrites in a microtubule-dependent, 3,5-dihydroxyphenylglycine-stimulated manner with similar kinetics to that of wild-type FMRP. Hence, polyribosome-free FMRP–mRNP complexes travel on microtubules and wait for activity-dependent translational derepression at the site of function. The dual participation of FMRP in dormant mRNPs and polyribosomes suggests distinct roles of FMRP in dendritic transport and translational regulation, two distinct phases that control local protein production to accommodate synaptic plasticity.

scholarly journals Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP)

2008 ◽  
Vol 63 (1) ◽  
pp. 40-51 ◽  
Author(s):  
Doron Gothelf ◽  
Joyce A. Furfaro ◽  
Fumiko Hoeft ◽  
Mark A. Eckert ◽  
Scott S. Hall ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Aberrant Behavior ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein

scholarly journals FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis

2020 ◽  
Author(s):  
Katherine Bonnycastle ◽  
Peter C. Kind ◽  
Michael A. Cousin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Neuronal Activity ◽  
Neurotransmitter Release ◽  
Fragile X ◽  
High Frequency Stimulation ◽  
Neuronal Cultures ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Activity Dependent

ABSTRACTSynaptic vesicle (SV) recycling is essential for the maintenance of neurotransmission, with a number of neurodevelopmental disorders linked to defects in this process. Fragile X syndrome (FXS) results from a loss of fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. FMRP is an established translation repressor, however it also has translation-independent presynaptic roles, including regulation of the trafficking and function of specific ion channels. Since defects in SV recycling are exacerbated during intense neuronal activity, we investigated whether these events were disproportionately affected by the absence of FMRP. We revealed that primary neuronal cultures from a Fmr1 knockout rat model display a specific defect in activity-dependent bulk endocytosis (ADBE). ADBE is dominant during intense neuronal activity, and this defect resulted in an inability of Fmr1 knockout neurons to sustain SV recycling during trains of high frequency stimulation. Using a molecular replacement strategy, we revealed that a human FMRP interaction mutant failed to correct ADBE dysfunction in knockout neurons. Therefore, FMRP performs a key role in sustaining neurotransmitter release via selective control of the endocytosis mode, ADBE.SIGNIFICANCE STATEMENTLoss of fragile X mental retardation protein (FMRP) results in fragile X syndrome (FXS), however whether its loss has a direct role in neurotransmitter release remains a matter of debate. We demonstrate that neurons lacking FMRP display a specific defect in a mechanism that sustains neurotransmitter release during intense neuronal firing, called activity-dependent bulk endocytosis (ADBE). This discovery provides key insights into mechanisms of brain communication that occur due to loss of FMRP function. Importantly it also reveals ADBE as a potential therapeutic target to correct the circuit hyperexcitabilty observed in FXS.

scholarly journals Molecular Biomarkers in Fragile X Syndrome

2019 ◽  
Vol 9 (5) ◽  
pp. 96 ◽  
Author(s):  
Zafarullah ◽  
Tassone
Keyword(s):  
Clinical Trials ◽  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Molecular Biomarkers ◽  
Synaptic Function ◽  
Primary Role ◽  
Fragile X Mental Retardation

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5’ untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene causes methylation of the promoter with consequent silencing of the gene, ultimately leading to the loss of the encoded fragile X mental retardation 1 protein, FMRP. FMRP is an RNA binding protein that plays a primary role as a repressor of translation of various mRNAs, many of which are involved in the maintenance and development of neuronal synaptic function and plasticity. In addition to intellectual disability, patients with FXS face several behavioral challenges, including anxiety, hyperactivity, seizures, repetitive behavior, and problems with executive and language performance. Currently, there is no cure or approved medication for the treatment of the underlying causes of FXS, but in the past few years, our knowledge about the proteins and pathways that are dysregulated by the loss of FMRP has increased, leading to clinical trials and to the path of developing molecular biomarkers for identifying potential targets for therapies. In this paper, we review candidate molecular biomarkers that have been identified in preclinical studies in the FXS mouse animal model and are now under validation for human applications or have already made their way to clinical trials.

Metabotropic Receptor-Dependent Long-Term Depression Persists in the Absence of Protein Synthesis in the Mouse Model of Fragile X Syndrome

2006 ◽  
Vol 95 (5) ◽  
pp. 3291-3295 ◽  
Author(s):  
Elena D. Nosyreva ◽  
Kimberly M. Huber
Keyword(s):  
Protein Synthesis ◽  
Mental Retardation ◽  
Mouse Model ◽  
Fragile X Syndrome ◽  
Rna Binding ◽  
Fragile X ◽  
Surface Expression ◽  
Long Term Depression ◽  
Fragile X Mental Retardation

Fragile X syndrome (FXS), a form of human mental retardation, is caused by loss of function mutations in the fragile X mental retardation gene ( FMR1). The protein product of FMR1, fragile X mental retardation protein (FMRP) is an RNA-binding protein and may function as a translational suppressor. Metabotropic glutamate receptor–dependent long-term depression (mGluR-LTD) in hippocampal area CA1 is a form of synaptic plasticity that relies on dendritic protein synthesis. mGluR-LTD is enhanced in the mouse model of FXS, Fmr1 knockout (KO) mice, suggesting that FMRP negatively regulates translation of proteins required for LTD. Here we examine the synaptic and cellular mechanisms of mGluR-LTD in KO mice and find that mGluR-LTD no longer requires new protein synthesis, in contrast to wild-type (WT) mice. We further show that mGluR-LTD in KO and WT mice is associated with decreases in AMPA receptor (AMPAR) surface expression, indicating a similar postsynaptic expression mechanism. However, like LTD, mGluR-induced decreases in AMPAR surface expression in KO mice persist in protein synthesis inhibitors. These results are consistent with recent findings of elevated protein synthesis rates and synaptic protein levels in Fmr1 KO mice and suggest that these elevated levels of synaptic proteins are available to increase the persistence of LTD without de novo protein synthesis.

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