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https://www.readbyqxmd.com/read/29140688/an-rna-chemical-proteomics-approach-reveals-the-n6-methyladenosine-m6a-regulated-protein-rna-interactome
#1
A Emilia Arguello, Amanda N DeLiberto, Ralph Kleiner
Epitranscriptomic RNA modifications can regulate mRNA function; however, there is a major gap in our understanding of the biochemical mechanisms mediating their effects. Here, we develop a chemical proteomics approach relying upon photo-crosslinking with synthetic diazirine-containing RNA probes and quantitative proteomics to profile RNA-protein interactions regulated by N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic RNA. In addition to identifying YTH domain-containing proteins and ALKBH5, known interactors of this modification, we find that FMR1 and LRPPRC, two proteins associated with human disease, 'read' this modification...
November 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29133950/treating-a-novel-plasticity-defect-rescues-episodic-memory-in-fragile-x-model-mice
#2
W Wang, B M Cox, Y Jia, A A Le, C D Cox, K M Jung, B Hou, D Piomelli, C M Gall, Gary Lynch
Episodic memory, a fundamental component of human cognition, is significantly impaired in autism. We believe we report the first evidence for this problem in the Fmr1-knockout (KO) mouse model of Fragile X syndrome and describe potentially treatable underlying causes. The hippocampus is critical for the formation and use of episodes, with semantic (cue identity) information relayed to the structure via the lateral perforant path (LPP). The unusual form of synaptic plasticity expressed by the LPP (lppLTP) was profoundly impaired in Fmr1-KOs relative to wild-type mice...
November 14, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29116166/multiple-behavior-phenotypes-of-the-fragile-x-syndrome-mouse-model-respond-to-chronic-inhibition-of-phosphodiesterase-4d-pde4d
#3
Mark E Gurney, Patricia Cogram, Robert M Deacon, Christopher Rex, Michael Tranfaglia
Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment of adult male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved social interaction, and improved natural behaviors such as nesting and marble burying as well as dendritic spine morphology...
November 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29114038/aberrant-rac1-cofilin-signaling-mediates-defects-in-dendritic-spines-synaptic-function-and-sensory-perception-in-fragile-x-syndrome
#4
Alexander Pyronneau, Qionger He, Jee-Yeon Hwang, Morgan Porch, Anis Contractor, R Suzanne Zukin
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and a leading cause of autism. FXS is caused by a trinucleotide expansion in the gene FMR1 on the X chromosome. The neuroanatomical hallmark of FXS is an overabundance of immature dendritic spines, a factor thought to underlie synaptic dysfunction and impaired cognition. We showed that aberrantly increased activity of the Rho GTPase Rac1 inhibited the actin-depolymerizing factor cofilin, a major determinant of dendritic spine structure, and caused disease-associated spine abnormalities in the somatosensory cortex of FXS model mice...
November 7, 2017: Science Signaling
https://www.readbyqxmd.com/read/29114037/reducing-eif4e-eif4g-interactions-restores-the-balance-between-protein-synthesis-and-actin-dynamics-in-fragile-x-syndrome-model-mice
#5
Emanuela Santini, Thu N Huynh, Francesco Longo, So Yeon Koo, Edward Mojica, Laura D'Andrea, Claudia Bagni, Eric Klann
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism spectrum disorder. FXS is caused by silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP), an mRNA-binding protein that represses the translation of its target mRNAs. One mechanism by which FMRP represses translation is through its association with cytoplasmic FMRP-interacting protein 1 (CYFIP1), which subsequently sequesters and inhibits eukaryotic initiation factor 4E (eIF4E). CYFIP1 shuttles between the FMRP-eIF4E complex and the Rac1-Wave regulatory complex, thereby connecting translational regulation to actin dynamics and dendritic spine morphology, which are dysregulated in FXS model mice that lack FMRP...
November 7, 2017: Science Signaling
https://www.readbyqxmd.com/read/29112191/identifying-specific-prefrontal-neurons-that-contribute-to-autism-associated-abnormalities-in-physiology-and-social-behavior
#6
A C Brumback, I T Ellwood, C Kjaerby, J Iafrati, S Robinson, A T Lee, T Patel, S Nagaraj, F Davatolhagh, V S Sohal
Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing...
November 7, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29106525/loss-of-drosophila-fmrp-leads-to-alterations-in-energy-metabolism-and-mitochondrial-function
#7
Eliana D Weisz, Atif Towheed, Rachel E Monyak, Meridith S Toth, Douglas C Wallace, Thomas A Jongens
Fragile X Syndrome (FXS), the most prevalent form of inherited intellectual disability and the foremost monogenetic cause of autism, is caused by loss of expression of the FMR1 gene. Here, we show that dfmr1 modulates the global metabolome in Drosophila. Despite our previous discovery of increased brain insulin signaling, our results indicate that dfmr1 mutants have reduced carbohydrate and lipid stores and are hypersensitive to starvation stress. The observed metabolic deficits cannot be explained by feeding behavior, as we report that dfmr1 mutants are hyperphagic...
November 2, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29104533/cell-type-specific-mrna-dysregulation-in-hippocampal-ca1-pyramidal-neurons-of-the-fragile-x-syndrome-mouse-model
#8
Laura Ceolin, Nathalie Bouquier, Jihane Vitre-Boubaker, Stéphanie Rialle, Dany Severac, Emmanuel Valjent, Julie Perroy, Emma Puighermanal
Fragile X syndrome (FXS) is a genetic disorder due to the silencing of the Fmr1 gene, causing intellectual disability, seizures, hyperactivity, and social anxiety. All these symptoms result from the loss of expression of the RNA binding protein fragile X mental retardation protein (FMRP), which alters the neurodevelopmental program to abnormal wiring of specific circuits. Aberrant mRNAs translation associated with the loss of Fmr1 product is widely suspected to be in part the cause of FXS. However, precise gene expression changes involved in this disorder have yet to be defined...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29096020/elevated-progranulin-contributes-to-synaptic-and-learning-deficit-due-to-loss-of-fragile-x-mental-retardation-protein
#9
Kun Zhang, Yu-Jiao Li, Yanyan Guo, Kai-Yin Zheng, Qi Yang, Le Yang, Xin-Shang Wang, Qian Song, Tao Chen, Min Zhuo, Ming-Gao Zhao
Fragile X syndrome is an inheritable form of intellectual disability caused by loss of fragile X mental retardation protein (FMRP, encoded by the FMR1 gene). Absence of FMRP caused overexpression of progranulin (PGRN, encoded by GRN), a putative tumour necrosis factor receptor ligand. In the present study, we found that progranulin mRNA and protein were upregulated in the medial prefrontal cortex of Fmr1 knock-out mice. In Fmr1 knock-out mice, elevated progranulin caused insufficient dendritic spine pruning and late-phase long-term potentiation in the medial prefrontal cortex of Fmr1 knock-out mice...
October 31, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29075560/deletion-of-fmr1-results-in-sex-specific-changes-in-behavior
#10
Suzanne O Nolan, Conner D Reynolds, Gregory D Smith, Andrew J Holley, Brianna Escobar, Matthew A Chandler, Megan Volquardsen, Taylor Jefferson, Ashvini Pandian, Tileena Smith, Jessica Huebschman, Joaquin N Lugo
OBJECTIVE: In this study, we used a systemic Fmr1 knockout in order to investigate both genotype- and sex-specific differences across multiple measures of sociability, repetitive behaviors, activity levels, anxiety, and fear-related learning and memory. BACKGROUND: Fragile X syndrome is the most common monogenic cause of intellectual disability and autism. Few studies to date have examined sex differences in a mouse model of Fragile X syndrome, though clinical data support the idea of differences in both overall prevalence and phenotype between the sexes...
October 2017: Brain and Behavior
https://www.readbyqxmd.com/read/29062097/altered-surface-mglur5-dynamics-provoke-synaptic-nmdar-dysfunction-and-cognitive-defects-in-fmr1-knockout-mice
#11
Elisabetta Aloisi, Katy Le Corf, Julien Dupuis, Pei Zhang, Melanie Ginger, Virginie Labrousse, Michela Spatuzza, Matthias Georg Haberl, Lara Costa, Ryuichi Shigemoto, Anke Tappe-Theodor, Filippo Drago, Pier Vincenzo Piazza, Christophe Mulle, Laurent Groc, Lucia Ciranna, Maria Vincenza Catania, Andreas Frick
Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR...
October 24, 2017: Nature Communications
https://www.readbyqxmd.com/read/29061680/genetics-white-matter-and-cognition-the-effects-of-methylation-on-fmr1
#12
(no author information available yet)
No abstract text is available yet for this article.
October 24, 2017: Neurology
https://www.readbyqxmd.com/read/29054962/expanded-alleles-of-the-fmr1-gene-are-related-to-unexplained-recurrent-miscarriages
#13
Xin-Hua Wang, Xiao-Hua Song, Tong Li, Xing-Hua Diao, Qing-Chun Li, Xiang-Hui Zhang, Yan-Lin Wang, Xiao-Hui Deng
Up to 50% of recurrent miscarriage cases in women occur without an underlying etiology. In the current prospective case-control study, we determined the impact of CGG trinucleotide expansions of the FMR1 gene in 49 women with unexplained recurrent miscarriages. Case group consisted of women with 2 or more unexplained consecutive miscarriages. Blood samples were obtained and checked for the presence of expanded alleles of the FMR1 gene using polymerase chain reaction. Patients harboring the expanded allele, with a threshold set to 40 repeats, were further evaluated by sequencing...
October 20, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29040407/genetic-reduction-of-matrix-metalloproteinase-9-promotes-formation-of-perineuronal-nets-around-parvalbumin-expressing-interneurons-and-normalizes-auditory-cortex-responses-in-developing-fmr1-knock-out-mice
#14
Teresa H Wen, Sonia Afroz, Sarah M Reinhard, Arnold R Palacios, Kendal Tapia, Devin K Binder, Khaleel A Razak, Iryna M Ethell
Abnormal sensory responses associated with Fragile X Syndrome (FXS) and autism spectrum disorders include hypersensitivity and impaired habituation to repeated stimuli. Similar sensory deficits are also observed in adult Fmr1 knock-out (KO) mice and are reversed by genetic deletion of Matrix Metalloproteinase-9 (MMP-9) through yet unknown mechanisms. Here we present new evidence that impaired development of parvalbumin (PV)-expressing inhibitory interneurons may underlie hyper-responsiveness in auditory cortex of Fmr1 KO mice via MMP-9-dependent regulation of perineuronal nets (PNNs)...
October 13, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/29038238/delayed-maturation-of-fast-spiking-interneurons-is-rectified-by-activation-of-the-trkb-receptor-in-the-mouse-model-of-fragile-x-syndrome
#15
Toshihiro Nomura, Timothy F Musial, John J Marshall, Yiwen Zhu, Christine L Remmers, Jian Xu, Daniel A Nicholson, Anis Contractor
Fragile X syndrome (FXS) is a neurodevelopmental disorder that is a leading cause of inherited intellectual disability, and the most common known cause of autism spectrum disorder (ASD). FXS is broadly characterized by sensory hypersensitivity and several developmental alterations in synaptic and circuit function have been uncovered in the sensory cortex of the mouse model of FXS (Fmr1 KO). GABA mediated neurotransmission and fast-spiking (FS) GABAergic interneurons are central to cortical circuit development in the neonate...
October 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29036014/a-family-with-two-cases-of-melanocytic-tumors-and-fragile-x-syndrome
#16
Candice Lesage, Isabelle Coupier, Bernard Guillot
Fragile X syndrome (FXS), a leading cause of inherited intellectual disability, most commonly results from an expansion of the CGG trinucleotide repeat in the fragile X mental retardation 1 (FMR1) gene to more than 200 copies (full mutation). The FXS phenotype differs by sex and is associated with intellectual and cognitive impairment, characteristic physical features, epilepsy, and/or behavioral challenges including autism spectrum disorder. In this patient population, tumors involving blood cells, digestive organs, the central nervous system, and testes have been described, but melanocytic tumors have not been reported...
December 2017: Melanoma Research
https://www.readbyqxmd.com/read/29019321/beyond-excitation-inhibition-imbalance-in-multidimensional-models-of-neural-circuit-changes-in-brain-disorders
#17
Cian O'Donnell, J Tiago Gonçalves, Carlos Portera-Cailliau, Terrence J Sejnowski
A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here, we combined computational simulations with analysis of in vivo two-photon Ca(2+) imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: (1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; (2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; (3) The direction of circuit alterations in Fmr1 KO mice changes across development...
October 11, 2017: ELife
https://www.readbyqxmd.com/read/28972453/impaired-eye-contact-in-the-fmr1-premutation-is-not-associated-with-social-anxiety-or-the-broad-autism-phenotype
#18
Jessica Klusek, Alexis Ruber, Jane E Roberts
OBJECTIVE: The Fragile X Mental Retardation-1 (FMR1) premutation is a common genetic abnormality, affecting ~1:150 women in the United States. Clinical neuropsychologists are becoming increasingly aware of their role in the clinical management of the FMR1 premutation, which is associated with risk for a range of cognitive, executive, neuromotor, and psychological impairments, including neurodegenerative disease. This study investigated atypical eye contact as a critical neuropsychological phenotype associated with the FMR1 premutation...
October 3, 2017: Clinical Neuropsychologist
https://www.readbyqxmd.com/read/28971146/clinical-and-molecular-correlates-in-fragile-x-premutation-females
#19
Poonnada Jiraanont, Stefan R Sweha, Reem R AlOlaby, Marisol Silva, Hiu-Tung Tang, Blythe Durbin-Johnson, Andrea Schneider, Glenda M Espinal, Paul J Hagerman, Susan M Rivera, David Hessl, Randi J Hagerman, Nuanchan Chutabhakdikul, Flora Tassone
The prevalence of the fragile X premutation (55-200 CGG repeats) among the general population is relatively high, but there remains a lack of clear understanding of the links between molecular biomarkers and clinical outcomes. In this study we investigated the correlations between molecular measures (CGG repeat size, FMR1 mRNA, FMRP expression levels, and methylation status at the promoter region and in FREE2 site) and clinical phenotypes (anxiety, obsessive compulsive symptoms, depression and executive function deficits) in 36 adult premutation female carriers and compared to 24 normal control subjects...
June 2017: ENeurologicalSci
https://www.readbyqxmd.com/read/28967713/reduction-in-the-number-of-cgg-repeats-on-the-fmr1-gene-in-carriers-of-genetic-disorders-versus-noncarriers
#20
Alexandra Peyser, Tomer Singer, Christine Mullin, Avner Hershlag
OBJECTIVE: CGG repeat expansion on the fragile X mental retardation 1 (FMR1) gene is used to diagnose fragile X syndrome. Previous studies have discussed the correlation between the number of CGG repeats and its associated phenotypic components. The objective of this study is to determine whether the number of CGG repeats differ between carriers of genetic disorders versus noncarriers. METHODS: We performed a retrospective chart review of 2867 patients who received genetic screening at our fertility clinic between June 2013 and July 2015...
October 2, 2017: JBRA Assisted Reproduction
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