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https://www.readbyqxmd.com/read/28094958/magnetic-nanoparticle-based-mechanical-stimulation-for-restoration-of-mechano-sensitive-ion-channel-equilibrium-in-neural-networks
#1
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 micro-fabricated 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 17, 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
#2
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
#3
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
#4
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 4, 2017: Neuron
https://www.readbyqxmd.com/read/28025327/fmrp-dependent-mdm2-dephosphorylation-is-required-for-mef2-induced-synapse-elimination
#5
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
https://www.readbyqxmd.com/read/28005950/cgg-repeats-in-the-5-utr-of-fmr1-rna-regulate-translation-of-other-rnas-localized-in-the-same-rna-granules
#6
René Rovozzo, George Korza, Mei W Baker, Meng Li, Anita Bhattacharyya, Elisa Barbarese, John H Carson
CGG repeats in the 5'UTR of Fragile X Mental Retardation 1 (FMR1) RNA mediate RNA localization and translation in granules. Large expansions of CGG repeats (> 200 repeats) in FMR1, referred to as full mutations, are associated with fragile X syndrome (FXS). Smaller expansions (55-200 repeats), referred to as premutations, are associated with fragile X tremor ataxia syndrome (FXTAS) and fragile X premature ovarian insufficiency (FXPOI). TMPyP4 is a porphyrin ring compound that destabilizes CGG repeat RNA secondary structure...
2016: PloS One
https://www.readbyqxmd.com/read/27911744/dysregulation-of-mrna-localization-and-translation-in-genetic-disease
#7
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
#8
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...
January 26, 2017: Neuroscience
https://www.readbyqxmd.com/read/27881780/negative-allosteric-modulation-of-mglur5-partially-corrects-pathophysiology-in-a-mouse-model-of-rett-syndrome
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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/repeat-associated-non-aug-translation-from-antisense-ccg-repeats-in-fragile-x-tremor-ataxia-syndrome
#15
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...
December 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
#16
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
#17
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
#18
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
#19
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
#20
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
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