scholarly journals 120 Fragile X Syndrome Sharing Similar Neural Network Abnormalities as ADHD

CNS Spectrums ◽  
2018 ◽  
Vol 23 (1) ◽  
pp. 76-76
Author(s):  
Chunhui Yang ◽  
Carolyn Beebe Smith ◽  
Guoqiang Xing ◽  
Sandeep Gaonkar
Keyword(s):  
Neural Network ◽  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Rna Binding ◽  
Psychiatric Symptoms ◽  
Fragile X ◽  
Brain Regions ◽  
Brain Maturation ◽  
Null Mouse ◽  
Study Objective

AbstractTitleFragile X syndrome sharing similar neural network abnormalities as ADHDStudy Objective(s)The Fragile X syndrome (FXS) phenotype typically involves a variety of psychiatric symptoms, including features of autism, attention deficit/hyperactivity disorder (ADHD), anxiety, and aggression. Studies have shown that ADHD is characterized by multiple functional and structural neural network abnormalities including fronto-striatal, fronto-parieto-temporal, fronto-cerebellar and fronto-limbic networks (Rubia, 2014; Norman, 2017). Studies have shown that ADHD is characterized by a delay in structural brain maturation (Rubia, 2007). Absence of the FMR1 gene product Fragile X mental retardation protein (FMRP) results in FXS, an inherited form of mental retardation. FMRP is an RNA binding protein functioning as a nucleocytoplasmic shuttling. In a knockout mouse model of FXS (Fmr1 null), Qin, et al showed regionally selective effects on cerebral metabolic rates for glucose (rCMRglc) (Qin, 2002) and rates of cerebral protein synthesis (Qin, 2005). In the present study, we asked if there is a relationship between brain regions most vulnerable to the effects of the absence of FMRP in the Fmr1 null mouse, and if the distribution consistent with the structural and functional brain abnormalities in ADHD. We also asked if there is a difference between males and females in the regional distributions and the levels of the FXR mRNAs.MethodWe used 35S-labeled probes specific for the mRNAs to perform in situ hybridization on brains from male (n=4) and female (n=4) mice at 6 months of age. Flowing hybridization, brain sections were exposed to X-ray film and optical density were measured in nine brain regions on autoradiograms of sections hybridized to the probe.ResultsThe highest levels of expression we observed were in the cerebellum, granular layers of the hippocampus. Levels of expression were also high in CA1 pyramidal neurons of hippocampus, amygdala and granule layer of olfactory bulb. We found intermediate levels in the anterior hypothalamus and in cingulate and frontal cortex. Low levels of expression were found in thalamus and caudate. The distribution for the probe was similar in male and female mice, but we found a tendency for male mice to have higher levels than females.Funding AcknowledgementsNo funding.

scholarly journals FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Raeann Goering ◽  
Laura I Hudish ◽  
Bryan B Guzman ◽  
Nisha Raj ◽  
Gary J Bassell ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Rna Localization ◽  
Null Mouse ◽  
Rna Sequences ◽  
Rna Molecules ◽  
G Quadruplex

The sorting of RNA molecules to subcellular locations facilitates the activity of spatially restricted processes. We have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these transcripts contain an enrichment of G-quadruplex sequences in their 3′ UTRs, suggesting that FMRP recognizes them to promote RNA localization. We observed similar results in neurons derived from Fragile X Syndrome patients. We identified the RGG domain of FMRP as important for binding G-quadruplexes and the transport of G-quadruplex-containing transcripts. Finally, we found that the translation and localization targets of FMRP were distinct and that an FMRP mutant that is unable to bind ribosomes still promoted localization of G-quadruplex-containing messages. This suggests that these two regulatory modes of FMRP may be functionally separated. These results provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

scholarly journals New Targeted Treatments for Fragile X Syndrome

2019 ◽  
Vol 15 (4) ◽  
pp. 251-258 ◽  
Author(s):  
Dragana Protic ◽  
Maria J. Salcedo-Arellano ◽  
Jeanne Barbara Dy ◽  
Laura A. Potter ◽  
Randi J. Hagerman
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Behavioral Problems ◽  
Rna Binding ◽  
Fragile X ◽  
Symptomatic Treatment ◽  
Fmr1 Gene ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5’ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.

scholarly journals An “Omic” Overview of Fragile X Syndrome

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 433
Author(s):  
Olivier Dionne ◽  
François Corbin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Medical Problems ◽  
Biochemical Alterations ◽  
Fragile X Mental Retardation ◽  
Wide Range

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP (fragile X mental retardation protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focused on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into humans as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspective the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. This work presents a review of FMRP’s involvement on noteworthy molecular mechanisms that may ultimately contribute to various biochemical alterations composing the fragile X phenotype.

scholarly journals An ‘’Omic’’ Overview of Fragile X Syndrome

2021 ◽  
Author(s):  
Olivier Dionne ◽  
François Corbin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Approaches ◽  
Medical Problems ◽  
Fragile X Mental Retardation ◽  
Wide Range

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene, and consequently, in the absence of its encoded protein, FMRP (Fragile X Mental Retardation Protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focus on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into human, as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspectives the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. In this review, FMRP’s involvement on noteworthy molecular mechanisms are pointed out; ultimately contributing to various biochemicals alterations composing the fragile X phenotype.

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.

Learning-disabled Males With a Fragile X CGG Expansion in the Upper Premutation Size Range

PEDIATRICS ◽  
1996 ◽  
Vol 97 (1) ◽  
pp. 122-126
Author(s):  
Randi J. Hagerman ◽  
Louise W. Staley ◽  
Rebecca O'Conner ◽  
Kellie Lugenbeel ◽  
David Nelson ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Size Range ◽  
Cpg Island ◽  
Fragile X ◽  
Learning Disabled ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Responsible Gene ◽  
Repeat Segment

There is a broad spectrum of clinical involvement in both boys and girls affected by fragile X syndrome. Although this disorder is best known as the most common inherited cause of mental retardation, it also can manifest as learning disabilities in individuals with IQs in the broad range of normal. Boys are usually retarded, and girls are usually learning disabled with fragile X syndrome.1 The responsible gene, fragile X mental retardation 1 (FMR1), was isolated in 1991, and the mutation was found to involve expansion of a trinucleotide (CGG) repeat segment. Individuals with fragile X syndrome have a CGG expansion of more than 200 repeats associated with hypermethylation of both the expansion and an adjacent CpG island (full mutation).2,3

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