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https://www.readbyqxmd.com/read/28334053/new-insights-of-altered-lipid-profile-in-fragile-x-syndrome
#1
Artuela Çaku, Nabil G Seidah, Audrey Lortie, Nancy Gagné, Patrice Perron, Jean Dubé, Francois Corbin
BACKGROUND: Fragile X Syndrome (FXS) is the main genetic cause of autism and intellectual deficiency resulting the absence of the Fragile X Mental Retardation Protein (FMRP). Clinical picture is characterized by cognitive impairment associated with a broad spectrum of psychiatric comorbidities including autism spectrum disorders and attention-deficit/hyperactivity disorders. Some of these disorders have been associated with lipid abnormalities and lower cholesterol levels. Since lipids are important for neuronal development, we aim to investigate the lipid profile of French Canadian-FXS individuals and to identify the altered components of cholesterol metabolism as well as their association with clinical profile...
2017: PloS One
https://www.readbyqxmd.com/read/28330777/altered-visual-repetition-suppression-in-fragile-x-syndrome-new-evidence-from-erps-and-oscillatory-activity
#2
Simon Rigoulot, Inga S Knoth, Marc-Philippe Lafontaine, Phetsamone Vannasing, Philippe Major, Sébastien Jacquemont, Jacques L Michaud, Karim Jerbi, Sarah Lippe
Fragile X Syndrome (FXS) is a neurodevelopmental genetic disorder associated with cognitive and behavioural deficits. In particular, neuronal habituation processes have been shown to be altered in FXS patients. Yet, while such deficits have been primarily explored using auditory stimuli, less is known in the visual modality. Here, we investigated the putative alteration of repetition suppression using faces in FXS patients compared to controls that had the same age distribution. Electroencephalographic (EEG) signals were acquired while participants were presented with 18 different faces, each repeated ten times successively...
March 19, 2017: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/28329674/%C3%AE-arrestin2-couples-metabotropic-glutamate-receptor-5-to-neuronal-protein-synthesis-and-is-a-potential-target-to-treat-fragile-x
#3
Laura J Stoppel, Benjamin D Auerbach, Rebecca K Senter, Anthony R Preza, Robert J Lefkowitz, Mark F Bear
Synaptic protein synthesis is essential for modification of the brain by experience and is aberrant in several genetically defined disorders, notably fragile X (FX), a heritable cause of autism and intellectual disability. Neural activity directs local protein synthesis via activation of metabotropic glutamate receptor 5 (mGlu5), yet how mGlu5 couples to the intracellular signaling pathways that regulate mRNA translation is poorly understood. Here, we provide evidence that β-arrestin2 mediates mGlu5-stimulated protein synthesis in the hippocampus and show that genetic reduction of β-arrestin2 corrects aberrant synaptic plasticity and cognition in the Fmr1(-/y) mouse model of FX...
March 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28316753/a-resting-eeg-study-of-neocortical-hyperexcitability-and-altered-functional-connectivity-in-fragile-x-syndrome
#4
Jun Wang, Lauren E Ethridge, Matthew W Mosconi, Stormi P White, Devin K Binder, Ernest V Pedapati, Craig A Erickson, Matthew J Byerly, John A Sweeney
BACKGROUND: Cortical hyperexcitability due to abnormal fast-spiking inhibitory interneuron function has been documented in fmr1 KO mice, a mouse model of the fragile X syndrome which is the most common single gene cause of autism and intellectual disability. METHODS: We collected resting state dense-array electroencephalography data from 21 fragile X syndrome (FXS) patients and 21 age-matched healthy participants. RESULTS: FXS patients exhibited greater gamma frequency band power, which was correlated with social and sensory processing difficulties...
2017: Journal of Neurodevelopmental Disorders
https://www.readbyqxmd.com/read/28266018/cell-type-dependent-axonal-localization-of-translational-regulators-and-mrna-in-mouse-peripheral-olfactory-neurons
#5
Lulu I T Korsak, Katherine A Shepard, Michael R Akins
Local protein synthesis in mature axons may play a role in synaptic plasticity, axonal arborization, or functional diversity of the circuit. To gain insight into this question, we investigated the axonal localization of translational regulators and associated mRNAs in five parallel olfactory circuits, four in the main olfactory bulb and one in the accessory olfactory bulb. Axons in all four main olfactory bulb circuits exhibited axonal localization of Fragile X granules (FXGs), structures that comprise ribosomes, mRNA, and RNA binding proteins including the Fragile X protein FMRP (Fragile X mental retardation protein) and the related protein FXR2P...
March 7, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/28257890/a-novel-role-of-fragile-x-mental-retardation-protein-in-pre-mrna-alternative-splicing-through-rna-binding-protein-14
#6
Lin-Tao Zhou, Shun-Hua Ye, Hai-Xuan Yang, Yong-Ting Zhou, Qi-Hua Zhao, Wei-Wen Sun, Mei-Mei Gao, Yong-Hong Yi, Yue-Sheng Long
Fragile X mental retardation protein (FMRP), an important RNA-binding protein responsible for fragile X syndrome, is involved in posttranscriptional control of gene expression that links with brain development and synaptic functions. Here, we reveal a novel role of FMRP in pre-mRNA alternative splicing, a general event of posttranscriptional regulation. Using co-immunoprecipitation and immunofluorescence assays, we identified that FMRP interacts with an alternative-splicing-associated protein RNA-binding protein 14 (RBM14) in a RNA-dependent fashion, and the two proteins partially colocalize in the nuclei of hippocampal neurons...
February 28, 2017: Neuroscience
https://www.readbyqxmd.com/read/28223318/a-drosophila-model-of-fragile-x-syndrome-exhibits-defects-in-phagocytosis-by-innate-immune-cells
#7
Reed M O'Connor, Elizabeth F Stone, Charlotte R Wayne, Emily V Marcinkevicius, Matt Ulgherait, Rebecca Delventhal, Meghan M Pantalia, Vanessa M Hill, Clarice G Zhou, Sophie McAllister, Anna Chen, Jennifer S Ziegenfuss, Wesley B Grueber, Julie C Canman, Mimi M Shirasu-Hiza
Fragile X syndrome, the most common known monogenic cause of autism, results from the loss of FMR1, a conserved, ubiquitously expressed RNA-binding protein. Recent evidence suggests that Fragile X syndrome and other types of autism are associated with immune system defects. We found that Drosophila melanogaster Fmr1 mutants exhibit increased sensitivity to bacterial infection and decreased phagocytosis of bacteria by systemic immune cells. Using tissue-specific RNAi-mediated knockdown, we showed that Fmr1 plays a cell-autonomous role in the phagocytosis of bacteria...
March 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28218269/enhanced-expression-of-adcy1-underlies-aberrant-neuronal-signalling-and-behaviour-in-a-syndromic-autism-model
#8
Ferzin Sethna, Wei Feng, Qi Ding, Alfred J Robison, Yue Feng, Hongbing Wang
Fragile X syndrome (FXS), caused by the loss of functional FMRP, is a leading cause of autism. Neurons lacking FMRP show aberrant mRNA translation and intracellular signalling. Here, we identify that, in Fmr1 knockout neurons, type 1 adenylyl cyclase (Adcy1) mRNA translation is enhanced, leading to excessive production of ADCY1 protein and insensitivity to neuronal stimulation. Genetic reduction of Adcy1 normalizes the aberrant ERK1/2- and PI3K-mediated signalling, attenuates excessive protein synthesis and corrects dendritic spine abnormality in Fmr1 knockout mice...
February 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28213518/deficits-in-the-activity-of-presynaptic-%C3%AE-aminobutyric-acid-type-b-receptors-contribute-to-altered-neuronal-excitability-in-fragile-x-syndrome
#9
Ji-Yong Kang, Jayashree Chadchankar, Thuy N Vien, Michelle I Mighdoll, Thomas M Hyde, Robert J Mather, Tarek Z Deeb, Menelas N Pangalos, Nicholas J Brandon, John Dunlop, Stephen J Moss
The behavioral and anatomical deficits seen in Fragile X syndrome (FXS) are widely believed to result from imbalances in the relative strengths of excitatory and inhibitory neurotransmission. While modified neuronal excitability is thought to be of significance, the contribution that alterations in GABAergic inhibition play in the pathophysiology of FXS are ill-defined. Slow sustained neuronal inhibition is mediated by γ-aminobutyric acid type B (GABAB) receptors, which are heterodimeric G-protein coupled receptors constructed from R1a and R2 or R1b and R2 subunits...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28203608/modeling-fragile-x-syndrome-in-neurogenesis-an-unexpected-phenotype-and-a-novel-tool-for-future-therapies
#10
Barbara Bardoni, Maria Capovilla, Enzo Lalli
FMRP is an RNA-binding protein involved in synaptic translation. Its absence causes a form of intellectual disability, the Fragile X syndrome (FXS). Small neuroanatomical abnormalities, present both in human and mouse FMRP-deficient brains, suggest a subtle critical role of this protein in neurogenesis. Stable depletion of FMRP has been obtained in a mouse embryonic stem cell line Fmr1 (shFmr1 ES) that does not display morphological alterations, but an abnormal expression of a subset of genes mainly involved in neuronal differentiation and maturation...
2017: Neurogenesis (Austin, Tex.)
https://www.readbyqxmd.com/read/28183735/new-insights-into-the-regulatory-function-of-cyfip1-in-the-context-of-wave-and-fmrp-containing-complexes
#11
Sabiha Abekhoukh, H Bahar Sahin, Mauro Grossi, Samantha Zongaro, Thomas Maurin, Irene Madrigal, Daniele Kazue-Sugioka, Annick Raas-Rothschild, Mohamed Doulazmi, Pilar Carrera, Andrea Stachon, Steven Scherer, Maria Rita Drula Do Nascimento, Alain Trembleau, Ignacio Arroyo, Szatmari Peter, Isabel M Smith, Montserrat Milà, Adam C Smith, Angela Giangrande, Isabelle Caillé, Barbara Bardoni
CYtoplasmic FMRP Interacting Protein 1 (CYFIP1) is a candidate gene for intellectual disability (ID), autism, schizophrenia and epilepsy. It is a member of a family of proteins that is very conserved during evolution, sharing high homology with dCYFIP, its Drosophila homolog. CYFIP1 interacts with the Fragile X Mental Retardation Protein (FMRP), whose absence causes the Fragile X Syndrome, and with the translation initiation factor eIF4E. It is a member of the WAVE Regulatory Complex (WRC), thus representing a link between translational regulation and actin cytoskeleton...
February 9, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28173181/the-fmr1-promoter-is-selectively-hydroxymethylated-in-primary-neurons-of-fragile-x-syndrome-patients
#12
Rustam Esanov, Nadja S Andrade, Sarah Bennison, Claes Wahlestedt, Zane Zeier
No abstract text is available yet for this article.
November 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28140743/the-roles-of-motor-activity-and-environmental-enrichment-in-intellectual-disability
#13
Andrea De Giorgio
In people with intellectual disabilities, an enriched environment can stimulate the acquisition of motor skills and could partially repair neuronal impairment thanks to exploration and motor activity. A deficit in environmental and motor stimulation leads to low scores in intelligence tests and can cause serious motor skill problems. Although studies in humans do not give much evidence for explaining basic mechanisms of intellectual disability and for highlighting improvements due to enriched environmental stimulation, animal models have been valuable in the investigation of these conditions...
January 31, 2017: Somatosensory & Motor Research
https://www.readbyqxmd.com/read/28137726/molecular-analyses-of-neurogenic-defects-in-a-human-pluripotent-stem-cell-model-of-fragile-x-syndrome
#14
Michael J Boland, Kristopher L Nazor, Ha T Tran, Attila Szücs, Candace L Lynch, Ryder Paredes, Flora Tassone, Pietro Paolo Sanna, Randi J Hagerman, Jeanne F Loring
New research suggests that common pathways are altered in many neurodevelopmental disorders including autism spectrum disorder; however, little is known about early molecular events that contribute to the pathology of these diseases. The study of monogenic, neurodevelopmental disorders with a high incidence of autistic behaviours, such as fragile X syndrome, has the potential to identify genes and pathways that are dysregulated in autism spectrum disorder as well as fragile X syndrome. In vitro generation of human disease-relevant cell types provides the ability to investigate aspects of disease that are impossible to study in patients or animal models...
January 29, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28119500/interference-of-the-complex-between-ncs-1-and-ric8a-with-phenothiazines-regulates-synaptic-function-and-is-an-approach-for-fragile-x-syndrome
#15
Alicia Mansilla, Antonio Chaves-Sanjuan, Nuria E Campillo, Ourania Semelidou, Loreto Martínez-González, Lourdes Infantes, Juana María González-Rubio, Carmen Gil, Santiago Conde, Efthimios M C Skoulakis, Alberto Ferrús, Ana Martínez, María José Sánchez-Barrena
The protein complex formed by the Ca(2+) sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28094958/magnetic-nanoparticle-based-mechanical-stimulation-for-restoration-of-mechano-sensitive-ion-channel-equilibrium-in-neural-networks
#16
Andy Tay, Dino Di Carlo
Techniques offering remote control of neural activity with high spatiotemporal resolution and specificity are invaluable for deciphering the physiological roles of different classes of neurons in brain development and disease. Here, we first confirm that microfabricated substrates with enhanced magnetic field gradients allow for wireless stimulation of neural circuits dosed with magnetic nanoparticles using calcium indicator dyes. We also investigate the mechanism of mechano-transduction in this system and identify that N-type mechano-sensitive calcium ion channels play a key role in signal generation in response to magnetic force...
January 20, 2017: Nano Letters
https://www.readbyqxmd.com/read/28077511/altered-connectivity-and-synapse-maturation-of-the-hippocampal-mossy-fiber-pathway-in-a-mouse-model-of-the-fragile-x-syndrome
#17
F Scharkowski, Michael Frotscher, David Lutz, Martin Korte, Kristin Michaelsen-Preusse
The Fragile X syndrome (FXS) as the most common monogenetic cause of cognitive impairment and autism indicates how tightly the dysregulation of synapse development is linked to cognitive deficits. Symptoms of FXS include excessive adherence to patterns that point to compromised hippocampal network formation. Surprisingly, one of the most complex hippocampal synapses connecting the dentate gyrus (DG) to CA3 pyramidal neurons has not been analyzed in FXS yet. Intriguingly, we found altered synaptic function between DG and CA3 in a mouse model of FXS (fmr1 knockout [KO]) demonstrated by increased mossy fiber-dependent miniature excitatory postsynaptic current (mEPSC) frequency at CA3 pyramidal neurons together with increased connectivity between granule cells and CA3 neurons...
January 10, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28073926/mutations-of-pqbp1-in-renpenning-syndrome-promote-ubiquitin-mediated-degradation-of-fmrp-and-cause-synaptic-dysfunction
#18
Xiao-Yan Zhang, Junxia Qi, Yu-Qian Shen, Xian Liu, An Liu, Zikai Zhou, Junhai Han, Zi Chao Zhang
Renpenning syndrome is a group of X-linked intellectual disability (XLID) syndromes caused by mutations in human polyglutamine-binding protein 1 (PQBP1) gene. Little is known about the molecular pathogenesis of the various mutations that cause the notable variability in patients. In this study, we examine the cellular and synaptic functions of the most common mutations found in the patients: c.461_462delAG, c.459_462delAGAG, and c.463_464dupAG in an AG hexamer in PQBP1 exon 4. We discovered that PQBP1 c.459_462delAGAG and c...
January 10, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28065649/translation-of-expanded-cgg-repeats-into-fmrpolyg-is-pathogenic-and-may-contribute-to-fragile-x-tremor-ataxia-syndrome
#19
Chantal Sellier, Ronald A M Buijsen, Fang He, Sam Natla, Laura Jung, Philippe Tropel, Angeline Gaucherot, Hugues Jacobs, Hamid Meziane, Alexandre Vincent, Marie-France Champy, Tania Sorg, Guillaume Pavlovic, Marie Wattenhofer-Donze, Marie-Christine Birling, Mustapha Oulad-Abdelghani, Pascal Eberling, Frank Ruffenach, Mathilde Joint, Mathieu Anheim, Veronica Martinez-Cerdeno, Flora Tassone, Rob Willemsen, Renate K Hukema, Stéphane Viville, Cecile Martinat, Peter K Todd, Nicolas Charlet-Berguerand
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5' UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not...
January 18, 2017: Neuron
https://www.readbyqxmd.com/read/28025327/fmrp-dependent-mdm2-dephosphorylation-is-required-for-mef2-induced-synapse-elimination
#20
Nien-Pei Tsai, Julia R Wilkerson, Weirui Guo, Kimberly M Huber
The Myocyte Enhancer Factor 2 (MEF2) transcription factors suppress an excitatory synapse number by promoting degradation of the synaptic scaffold protein, postsynaptic density protein 95 (PSD-95), a process that is deficient in the mouse model of Fragile X Syndrome, Fmr1 KO. How MEF2 activation results in PSD-95 degradation and why this is defective in Fmr1 KO neurons is unknown. Here we report that MEF2 induces a Protein phosphatase 2A (PP2A)-mediated dephosphorylation of murine double minute-2 (Mdm2), the ubiquitin E3 ligase for PSD-95, which results in nuclear export and synaptic accumulation of Mdm2 as well as PSD-95 degradation and synapse elimination...
December 26, 2016: Human Molecular Genetics
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