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https://www.readbyqxmd.com/read/27911744/dysregulation-of-mrna-localization-and-translation-in-genetic-disease
#1
Eric T Wang, J Matthew Taliaferro, Ji-Ann Lee, Indulekha P Sudhakaran, Wilfried Rossoll, Christina Gross, Kathryn R Moss, Gary J Bassell
RNA-binding proteins (RBPs) acting at various steps in the post-transcriptional regulation of gene expression play crucial roles in neuronal development and synaptic plasticity. Genetic mutations affecting several RBPs and associated factors lead to diverse neurological symptoms, as characterized by neurodevelopmental and neuropsychiatric disorders, neuromuscular and neurodegenerative diseases, and can often be multisystemic diseases. We will highlight the physiological roles of a few specific proteins in molecular mechanisms of cytoplasmic mRNA regulation, and how these processes are dysregulated in genetic disease...
November 9, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27889578/molecular-neurobiology-of-mtor
#2
REVIEW
Katarzyna Switon, Katarzyna Kotulska, Aleksandra Janusz-Kaminska, Justyna Zmorzynska, Jacek Jaworski
Mammalian/mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that controls several important aspects of mammalian cell function. mTOR activity is modulated by various intra- and extracellular factors; in turn, mTOR changes rates of translation, transcription, protein degradation, cell signaling, metabolism, and cytoskeleton dynamics. mTOR has been repeatedly shown to participate in neuronal development and the proper functioning of mature neurons. Changes in mTOR activity are often observed in nervous system diseases, including genetic diseases (e...
November 23, 2016: Neuroscience
https://www.readbyqxmd.com/read/27881780/negative-allosteric-modulation-of-mglur5-partially-corrects-pathophysiology-in-a-mouse-model-of-rett-syndrome
#3
Jifang Tao, Hao Wu, Amanda A Coronado, Elizabeth de Laittre, Emily K Osterweil, Yi Zhang, Mark F Bear
: Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here, we report a test of the hypothesis of shared pathophysiology of RTT and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein-synthesis-dependent synaptic plasticity were similarly altered in area CA1 of Mecp2 KO mice...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27865451/astrocytic-contributions-to-synaptic-and-learning-abnormalities-in-a-mouse-model-of-fragile-x-syndrome
#4
Jennifer L Hodges, Xinzhu Yu, Anthony Gilmore, Hannah Bennett, Michelle Tjia, James F Perna, Chia-Chien Chen, Xiang Li, Ju Lu, Yi Zuo
BACKGROUND: Fragile X syndrome (FXS) is the most common type of mental retardation attributable to a single-gene mutation. It is caused by FMR1 gene silencing and the consequent loss of its protein product, fragile X mental retardation protein. Fmr1 global knockout (KO) mice recapitulate many behavioral and synaptic phenotypes associated with FXS. Abundant evidence suggests that astrocytes are important contributors to neurological diseases. This study investigates astrocytic contributions to the progression of synaptic abnormalities and learning impairments associated with FXS...
September 13, 2016: Biological Psychiatry
https://www.readbyqxmd.com/read/27860518/molecular-dynamics-of-fmrp-and-other-rna-binding-proteins-in-meg-01-differentiation-the-role-of-mrnp-complexes-in-non-neuronal-development
#5
M McCoy, D Poliquin-Duchesneau, F Corbin
Asymmetrically differentiating cells are formed with the aid of RNA-binding proteins (RBPs), which can bind, stabilize, regulate, and transport target mRNAs. The loss of RBPs in neurons may lead to severe neurodevelopmental diseases such as the Fragile X Syndrome with the absence of the Fragile X Mental Retardation Protein (FMRP). Because the latter is ubiquitous and shares many similarities with other RBPs involved in the development of peripheral cells, we suggest that FMRP would have a role in the differentiation of all tissues where it is expressed...
December 2016: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/27829268/altered-translational-control-of-fmrp-on-myelin-proteins-in-neuropsychiatric-disorders
#6
REVIEW
Se Jin Jeon, Jong Hoon Ryu, Geon Ho Bahn
Myelin is a specialized structure of the nervous system that both enhances electrical conductance and insulates neurons from external risk factors. In the central nervous system, polarized oligodendrocytes form myelin by wrapping processes in a spiral pattern around neuronal axons through myelin-related gene regulation. Since these events occur at a distance from the cell body, post-transcriptional control of gene expression has strategic advantage to fine-tune the overall regulation of protein contents in situ...
November 8, 2016: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/27818201/dna-damage-preceding-dopamine-neuron-degeneration-in-a53t-human-%C3%AE-synuclein-transgenic-mice
#7
Degui Wang, Tianyu Yu, Yongqiang Liu, Jun Yan, Yingli Guo, Yuhong Jing, Xuguang Yang, Yanfeng Song, Yingxia Tian
Defective DNA repair has been linked with age-associated neurodegenerative disorders. Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Whether damages to nuclear DNA contribute to neurodegeneration of PD still remain obscure. in this study we aim to explore whether nuclear DNA damage induce dopamine neuron degeneration in A53T human α-Synuclein over expressed mouse model. We investigated the effects of X-ray irradiation on A53T-α-Syn MEFs and A53T-α-Syn transgene mice...
December 2, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27777633/uncovering-obsessive-compulsive-disorder-risk-genes-in-a-pediatric-cohort-by-high-resolution-analysis-of-copy-number-variation
#8
Matthew J Gazzellone, Mehdi Zarrei, Christie L Burton, Susan Walker, Mohammed Uddin, S M Shaheen, Julie Coste, Rageen Rajendram, Reva J Schachter, Marlena Colasanto, Gregory L Hanna, David R Rosenberg, Noam Soreni, Kate D Fitzgerald, Christian R Marshall, Janet A Buchanan, Daniele Merico, Paul D Arnold, Stephen W Scherer
BACKGROUND: Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD. METHODS: We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0...
2016: Journal of Neurodevelopmental Disorders
https://www.readbyqxmd.com/read/27761921/ran-translation-from-antisense-ccg-repeats-in-fragile-x-tremor-ataxia-syndrome
#9
Amy Krans, Michael G Kearse, Peter K Todd
OBJECTIVE: Repeat associated non-AUG (RAN) translation drives production of toxic proteins from pathogenic repeat sequences in multiple untreatable neurodegenerative disorders. Fragile X-associated tremor/ataxia syndrome (FXTAS) is one such condition, resulting from a CGG trinucleotide repeat expansion in the 5' leader sequence of the FMR1 gene. RAN proteins from the CGG repeat accumulate in ubiquitinated inclusions in FXTAS patient brains and elicit toxicity. In addition to the CGG repeat, an antisense mRNA containing a CCG repeat is also transcribed from the FMR1 locus...
October 19, 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27748740/arbaclofen-in-children-and-adolescents-with-autism-spectrum-disorder-a-randomized-controlled-phase-2-trial
#10
Jeremy Veenstra-VanderWeele, Edwin H Cook, Bryan H King, Peter Zarevics, Maryann Cherubini, Karen Walton-Bowen, Mark F Bear, Paul P Wang, Randall L Carpenter
Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD. In animal models of FXS and of ASD, GABA-B agonists have improved both brain and behavioral phenotypes, including social behavior. A phase 2 randomized, placebo-controlled, crossover trial found that the GABA-B agonist arbaclofen improved social avoidance symptoms in FXS...
October 17, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27730449/integrated-transcriptome-analysis-of-human-ips-cells-derived-from-a-fragile-x-syndrome-patient-during-neuronal-differentiation
#11
Ping Lu, Xiaolong Chen, Yun Feng, Qiao Zeng, Cizhong Jiang, Xianmin Zhu, Guoping Fan, Zhigang Xue
Fragile X syndrome (FXS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile X mental retardation 1 (FMR1), leading to decreased or absent expression of its encoded fragile X mental retardation protein (FMRP). However, the global transcriptional alteration by FMRP deficiency has not been well characterized at single nucleotide resolution, i.e., RNA-seq. Here, we performed in-vitro neuronal differentiation of human induced pluripotent stem (iPS) cells that were derived from fibroblasts of a FXS patient (FXS-iPSC)...
October 11, 2016: Science China. Life Sciences
https://www.readbyqxmd.com/read/27713816/cgg-repeat-dynamics-and-fmr1-gene-silencing-in-fragile-x-syndrome-stem-cells-and-stem-cell-derived-neurons
#12
Yifan Zhou, Daman Kumari, Nicholas Sciascia, Karen Usdin
BACKGROUND: Fragile X syndrome (FXS), a common cause of intellectual disability and autism, results from the expansion of a CGG-repeat tract in the 5' untranslated region of the FMR1 gene to >200 repeats. Such expanded alleles, known as full mutation (FM) alleles, are epigenetically silenced in differentiated cells thus resulting in the loss of FMRP, a protein important for learning and memory. The timing of repeat expansion and FMR1 gene silencing is controversial. METHODS: We monitored the repeat size and methylation status of FMR1 alleles with expanded CGG repeats in patient-derived induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) that were grown for extended period of time either as stem cells or differentiated into neurons...
2016: Molecular Autism
https://www.readbyqxmd.com/read/27690107/modeling-fragile-x-syndrome-using-human-pluripotent-stem-cells
#13
Hagar Mor-Shaked, Rachel Eiges
Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from a loss-of-function mutation by a CGG repeat expansion at the 5' untranslated region of the X-linked fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeats beyond 200 copies results in protein deficiency by leading to aberrant methylation of the FMR1 promoter and the switch from active to repressive histone modifications. Additionally, the CGGs become increasingly unstable, resulting in high degree of variation in expansion size between and within tissues of affected individuals...
2016: Genes
https://www.readbyqxmd.com/read/27683892/developmental-experience-dependent-plasticity-in-the-first-synapse-of-the-drosophila-olfactory-circuit
#14
REVIEW
Randall M Golovin, Kendal Broadie
Evidence accumulating over the past 15 years soundly refutes the dogma that the Drosophila nervous system is hardwired. The preponderance of studies reveals activity-dependent neural circuit refinement driving optimization of behavioral outputs. We describe developmental, sensory input-dependent plasticity in the brain olfactory antennal lobe, which we term long-term central adaption (LTCA). LTCA is evoked by prolonged exposure to an odorant during the first week of posteclosion life, resulting in a persistently decreased response to aversive odors and an enhanced response to attractive odors...
December 1, 2016: Journal of Neurophysiology
https://www.readbyqxmd.com/read/27664080/depletion-of-the-fragile-x-mental-retardation-protein-in-embryonic-stem-cells-alters-the-kinetics-of-neurogenesis
#15
Olfa Khalfallah, Marielle Jarjat, Laetitia Davidovic, Nicolas Nottet, Sandrine Cestèle, Massimo Mantegazza, Barbara Bardoni
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a leading cause of autism. FXS is due to the silencing of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein mainly involved in translational control, dendritic spine morphology and synaptic plasticity. Despite extensive studies, there is currently no cure for FXS. With the purpose to decipher the initial molecular events leading to this pathology, we developed a stem-cell-based disease model by knocking-down the expression of Fmr1 in mouse embryonic stem cells (ESCs)...
September 24, 2016: Stem Cells
https://www.readbyqxmd.com/read/27663742/elevated-erk-p90-ribosomal-s6-kinase-activity-underlies-audiogenic-seizure-susceptibility-in-fragile-x-mice
#16
Kirsty Sawicka, Alexander Pyronneau, Miranda Chao, Michael V L Bennett, R Suzanne Zukin
Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27643955/splice-form-dependent-regulation-of-axonal-arbor-complexity-by-fmrp
#17
Stephanie E Zimmer, Steven G Doll, A Denise R Garcia, Michael R Akins
The autism-related protein Fragile X mental retardation protein (FMRP) is an RNA binding protein that plays important roles during both nervous system development and experience dependent plasticity. Alternative splicing of the Fmr1 locus gives rise to 12 different FMRP splice forms that differ in the functional and regulatory domains they contain as well as in their expression profile among brain regions and across development. Complete loss of FMRP leads to morphological and functional changes in neurons, including an increase in the size and complexity of the axonal arbor...
September 19, 2016: Developmental Neurobiology
https://www.readbyqxmd.com/read/27605532/dynamic-balance-of-excitation-and-inhibition-rapidly-modulates-spike-probability-and-precision-in-feed-forward-hippocampal-circuits
#18
Sarah Wahlstrom-Helgren, Vitaly A Klyachko
Feed-forward inhibitory (FFI) circuits are important for many information-processing functions. FFI circuit operations critically depend on the balance and timing between the excitatory and inhibitory components, which undergo rapid dynamic changes during neural activity due to short-term plasticity (STP) of both components. How dynamic changes in excitation/inhibition (E/I) balance during spike trains influence FFI circuit operations remains poorly understood. In the current study we examined the role of STP in the FFI circuit functions in the mouse hippocampus...
December 1, 2016: Journal of Neurophysiology
https://www.readbyqxmd.com/read/27604541/fmrp-expression-levels-in-mouse-central-nervous-system-neurons-determine-behavioral-phenotype
#19
Jason Arsenault, Shervin Gholizadeh, Yosuke Niibori, Laura K Pacey, Sebok K Halder, Enea Koxhioni, Ayumu Konno, Hirokazu Hirai, David R Hampson
Fragile X mental retardation protein (FMRP) is absent or highly reduced in Fragile X Syndrome, a genetic disorder causing cognitive impairment and autistic behaviors. Previous proof-of-principle studies have demonstrated that restoring FMRP in the brain using viral vectors can improve pathological abnormalities in mouse models of fragile X. However, unlike small molecule drugs where the dose can readily be adjusted during treatment, viral vector-based biological therapeutic drugs present challenges in terms of achieving optimal dosing and expression levels...
September 7, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27599747/the-fmr1-promoter-is-selectively-hydroxymethylated-in-primary-neurons-of-fragile-x-syndrome-patients
#20
Rustam Esanov, Nadja S Andrade, Sarah Bennison, Claes Wahlestedt, Zane Zeier
Fragile X syndrome (FXS) results from a repeat expansion mutation near the FMR1 gene promoter and is the most common form of heritable intellectual disability and autism. Full mutations larger than 200 CGG repeats trigger FMR1 heterochromatinization and loss of gene expression, which is primarily responsible for the pathological features of FXS . In contrast, smaller pre-mutations of 55-200 CGG are associated with FMR1 overexpression and Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative condition...
September 5, 2016: Human Molecular Genetics
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