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C9orf72

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https://www.readbyqxmd.com/read/28093491/early-microgliosis-precedes-neuronal-loss-and-behavioural-impairment-in-mice-with-a-frontotemporal-dementia-causing-chmp2b-mutation
#1
Emma L Clayton, Renzo Mancuso, Troels Tolstrup Nielsen, Sarah Mizielinska, Holly Holmes, Nicholas Powell, Frances Norona, Jytte Overgaard Larsen, Carmelo Milioto, Katherine M Wilson, Mark F Lythgoe, Sebastian Ourselin, Jörgen E Nielsen, Peter Johannsen, Ida Holm, John Collinge, A Frej, Peter L Oliver, Diego Gomez-Nicola, Adrian M Isaacs
Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD...
January 16, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28089114/genetic-epidemiology-of-motor-neuron-disease-associated-variants-in-the-scottish-population
#2
Holly A Black, Danielle J Leighton, Elaine M Cleary, Elaine Rose, Laura Stephenson, Shuna Colville, David Ross, Jon Warner, Mary Porteous, George H Gorrie, Robert Swingler, David Goldstein, Matthew B Harms, Peter Connick, Suvankar Pal, Timothy J Aitman, Siddharthan Chandran
Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant...
December 21, 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/28088213/glycine-alanine-dipeptide-repeat-protein-contributes-to-toxicity-in-a-zebrafish-model-of-c9orf72-associated-neurodegeneration
#3
Yu Ohki, Andrea Wenninger-Weinzierl, Alexander Hruscha, Kazuhide Asakawa, Koichi Kawakami, Christian Haass, Dieter Edbauer, Bettina Schmid
BACKGROUND: The most frequent genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the expansion of a GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 (C9orf72) locus. The pathological hallmarks observed in C9orf72 repeat expansion carriers are the formation of RNA foci and deposition of dipeptide repeat (DPR) proteins derived from repeat associated non-ATG (RAN) translation. Currently, it is unclear whether formation of RNA foci, DPR translation products, or partial loss of C9orf72 predominantly drive neurotoxicity in vivo...
January 14, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28087719/genetics-insight-into-the-amyotrophic-lateral-sclerosis-frontotemporal-dementia-spectrum
#4
REVIEW
Ai-Ling Ji, Xia Zhang, Wei-Wei Chen, Wen-Juan Huang
Recent genetic discoveries have dramatically changed our understanding of two major neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are common, devastating diseases of the brain. For decades, ALS and FTD were classified as movement and cognitive disorders, respectively, due to their distinct clinical phenotypes. The recent identification of chromosome 9 open reading frame 72 (C9orf72) as the major gene causative of familial forms of ALS and FTD uncovered a new reality of a continuous FTD/ALS spectrum...
January 13, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28072389/suppression-of-c9orf72-rna-repeat-induced-neurotoxicity-by-the-als-associated-rna-binding-protein-zfp106
#5
Barbara Celona, John von Dollen, Sarat C Vatsavayai, Risa Kashima, Jeffrey R Johnson, Amy A Tang, Akiko Hata, Bruce L Miller, Eric J Huang, Nevan J Krogan, William W Seeley, Brian L Black
Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA forms aggregates that sequester RNA binding proteins, leading to altered RNA metabolism in motor neurons. Here, we identify the zinc finger protein Zfp106 as a specific GGGGCC RNA repeat-binding protein, and using affinity purification-mass spectrometry, we show that Zfp106 interacts with multiple other RNA binding proteins, including the ALS-associated factors TDP-43 and FUS...
January 10, 2017: ELife
https://www.readbyqxmd.com/read/28069952/toxic-prn-poly-dipeptides-encoded-by-the-c9orf72-repeat-expansion-block-nuclear-import-and-export
#6
Kevin Y Shi, Eiichiro Mori, Zehra F Nizami, Yi Lin, Masato Kato, Siheng Xiang, Leeju C Wu, Ming Ding, Yonghao Yu, Joseph G Gall, Steven L McKnight
The toxic proline:arginine (PRn) poly-dipeptide encoded by the (GGGGCC)n repeat expansion in the C9orf72 form of heritable amyotrophic lateral sclerosis (ALS) binds to the central channel of the nuclear pore and inhibits the movement of macromolecules into and out of the nucleus. The PRn poly-dipeptide binds to polymeric forms of the phenylalanine:glycine (FG) repeat domain, which is shared by several proteins of the nuclear pore complex, including those in the central channel. A method of chemical footprinting was used to characterize labile, cross-β polymers formed from the FG domain of the Nup54 protein...
January 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28057713/genetic-epidemiology-of-amyotrophic-lateral-sclerosis-a-systematic-review-and-meta-analysis
#7
Zhang-Yu Zou, Zhi-Rui Zhou, Chun-Hui Che, Chang-Yun Liu, Rao-Li He, Hua-Pin Huang
BACKGROUND: Genetic studies have shown that C9orf72, SOD1, TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). Here, we performed a meta-analysis to determine the mutation frequencies of these major ALS-related genes in patients with ALS. METHODS: We performed an extensive literature research to identify all original articles reporting frequencies of C9orf72, SOD1, TARDBP and FUS mutations in ALS. The mutation frequency and effect size of each study were combined...
January 5, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/28057298/amyotrophic-lateral-sclerosis-pathogenesis-converges-on-defects-in-protein-homeostasis-associated-with-tdp-43-mislocalization-and-proteasome-mediated-degradation-overload
#8
G Lin, D Mao, H J Bellen
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects upper and/or lower motor neurons. It usually affects people between the ages of 40-70. The average life expectancy is about 3-5 years after diagnosis and there is no effective cure available. Identification of variants in more than 20 different loci has provided insight into the pathogenic molecular mechanisms mediating disease pathogenesis. In this review, we focus on seven ALS-causing genes: TDP-43, FUS, C9orf72, VCP, UBQLN2, VAPB and SOD-1, which encompass about 90% of the variants causing familial ALS...
2017: Current Topics in Developmental Biology
https://www.readbyqxmd.com/read/28040728/cytoplasmic-poly-ga-aggregates-impair-nuclear-import-of-tdp-43-in-c9orf72-als-ftld
#9
Bahram Khosravi, Hannelore Hartmann, Stephanie May, Christoph Möhl, Helena Ederle, Meike Michaelsen, Martin H Schludi, Dorothee Dormann, Dieter Edbauer
A repeat expansion in the non-coding region of C9orf72 gene is the most common mutation causing frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Sense and antisense transcripts are translated into aggregating dipeptide repeat (DPR) proteins in all reading frames (poly-GA,-GP,-GR,-PA and -PR) through an unconventional mechanism. How these changes contribute to cytoplasmic mislocalization and aggregation of TDP-43 and thereby ultimately lead to neuron loss remains unclear. The repeat RNA itself and poly-GR/PR have been linked to impaired nucleocytoplasmic transport...
December 30, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28029704/dynamic-mislocalizations-of-nuclear-pore-complex-proteins-after-focal-cerebral-ischemia-in-rat
#10
Qian Li, Yasuyuki Ohta, Toru Yamashita, Jingwei Shang, Kentaro Deguchi, Tian Feng, Kota Sato, Nozomi Hishikawa, Yumiko Nakano, Koji Abe
Nuclear pore complexes (NPCs) play an important role in coordinating the transport of proteins and nucleic acids between the nucleus and cytoplasm, and are therefore essential for maintaining normal cellular function and liability. In the present study, we investigated the temporal immunohistochemical distribution of five representative components of NPCs-Ran GTPase-activating protein 1 (RanGap1), glycoprotein-210 (Gp210), nucleoporin 205 (Nup205), nucleoporin 107 (Nup107), and nucleoporin 50 (Nup50)-after 90 min of transient middle cerebral artery occlusion (tMCAO) up to 28 days after the reperfusion in rat brains...
December 28, 2016: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28010125/proposed-association-between-the-hexanucleotide-repeat-of-c9orf72-and-opposability-index-of-the-thumb
#11
Zhongbo Chen, Kuang Lin, Jeffrey D Macklis, Ammar Al-Chalabi
OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by motor neuron and sub-cerebral projection neuron degeneration. We sought to explore the particular susceptibility of humans to neurodegeneration and whether any characteristic human features might predispose to selective vulnerability of the critical motor circuitry in ALS. The pathophysiology of the C9orf72 repeat is not yet understood, despite its role as a common cause of ALS and frontotemporal dementia. METHODS: We examined the development of the monosynaptic cortico-motoneuronal system, key to skilled hand movements, measured by the thumb opposability index, and its relationship to the C9orf72 hexanucleotide repeat expansion, a strong predisposing factor for neurodegeneration, using the genomic tool BLAST...
December 23, 2016: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28009271/bidirectional-transcriptional-inhibition-as-therapy-for-als-ftd-caused-by-repeat-expansion-in-c9orf72
#12
Jie Jiang, Don W Cleveland
Hexanucleotide repeat expansion in the bi-directionally transcribed C9orf72 gene is the most frequent cause of familial ALS and frontotemporal dementia (FTD). Kramer et al. (2016) report in Science that targeted reduction in the transcription elongation factor SUPT4H1/SUPT5H reduces both sense and antisense repeat-containing RNAs and their associated neurodegeneration.
December 21, 2016: Neuron
https://www.readbyqxmd.com/read/28005462/recognition-of-c9orf72-mutant-rna-by-single-stranded-silencing-rnas
#13
Jiaxin Hu, Frank Rigo, Thazha P Prakash, David R Corey
Mutations within the chromosome 9 open reading frame 72 (c9orf72) gene are associated with both familial amyotrophic lateral sclerosis and frontotemporal dementia. The mutation leads to an expanded GGGGCC hexanucleotide repeat within the first intron of c9orf72 and an expanded CCCCGG repeat within a corresponding antisense transcript. Both the mutant intronic and antisense RNAs have been implicated in disease. We have previously reported that duplex RNAs complementary to the repeats can recognize disease-causing RNA and block detection of nuclear foci formed by the mutant transcripts...
December 22, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28003435/genetic-compendium-of-1511-human-brains-available-through-the-uk-medical-research-council-brain-banks-network-resource
#14
Michael J Keogh, Wei Wei, Ian Wilson, Jon Coxhead, Sarah Ryan, Sara Rollinson, Helen Griffin, Marzena Kurzawa-Akanbi, Mauro Santibanez-Koref, Kevin Talbot, Martin R Turner, Chris-Anne McKenzie, Claire Troakes, Johannes Attems, Colin Smith, Safa Al Sarraj, Chris M Morris, Olaf Ansorge, Stuart Pickering-Brown, James W Ironside, Patrick F Chinnery
Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368)...
January 2017: Genome Research
https://www.readbyqxmd.com/read/27999880/-pathomechanisms-and-clinical-aspects-of-frontotemporal-lobar-degeneration
#15
REVIEW
K Bürger, T Arzberger, J Stephan, J Levin, D Edbauer
BACKGROUND: Frontotemporal lobar degeneration (FTLD) includes a spectrum of heterogeneous clinical and neuropathological diseases. In a strict sense this includes the behavioral variant of frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) and both variants can be associated with amyotrophic lateral sclerosis (FTD-ALS). In a broader sense FTLD also includes progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). In recent years the strong genetic component of FTLD has become increasingly clear...
December 20, 2016: Der Nervenarzt
https://www.readbyqxmd.com/read/27995069/longitudinal-imaging-in-c9orf72-mutation-carriers-relationship-to-phenotype
#16
Mary Kay Floeter, Devin Bageac, Laura E Danielian, Laura E Braun, Bryan J Traynor, Justin Y Kwan
Expansion mutations in the C9orf72 gene may cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or mixtures of the two clinical phenotypes. Different imaging findings have been described for C9orf72-associated diseases in comparison with sporadic patients with the same phenotypes, but it is uncertain whether different phenotypes have a common genotype-associated imaging signature. To address this question, 27 unrelated C9orf72 expansion mutation carriers (C9 +) with varied phenotypes, 28 age-matched healthy controls and 22 patients with sporadic ALS (sALS) underwent 3T MRI scanning and clinical phenotyping...
2016: NeuroImage: Clinical
https://www.readbyqxmd.com/read/27982083/netdiff-bayesian-model-selection-for-differential-gene-regulatory-network-inference
#17
Thomas Thorne
Differential networks allow us to better understand the changes in cellular processes that are exhibited in conditions of interest, identifying variations in gene regulation or protein interaction between, for example, cases and controls, or in response to external stimuli. Here we present a novel methodology for the inference of differential gene regulatory networks from gene expression microarray data. Specifically we apply a Bayesian model selection approach to compare models of conserved and varying network structure, and use Gaussian graphical models to represent the network structures...
December 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27978769/genetic-analysis-of-patients-with-familial-and-sporadic-amyotrophic-lateral-sclerosis-in-a-brazilian-research-center
#18
Gerson Chadi, Jessica Ruivo Maximino, Frederico Mennucci de Haidar Jorge, FabríCIO Castro dE Borba, Joyce Meire Gilio, Dagoberto Callegaro, Camila GalvãO Lopes, Samantha Nakamura Dos Santos, Gabriela Natania Sales Rebelo
OBJECTIVE: To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. METHODS: Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses...
December 15, 2016: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/27956443/motor-neuron-disease-biomarker-development-for-an-expanding-cerebral-syndrome
#19
Martin R Turner
Descriptions of motor neuron disease (MND) documented more than a century ago remain instantly recognisable to the physician. The muscle weakness, typically with signs of upper and lower motor neuron dysfunction, is uniquely relentless. Over the last 30 years, a wider cerebral pathology has emerged, despite the lack of overt cognitive impairment in the majority of patients. From the initial linkage of a small number of cases to mutations in SOD1, diverse cellular pathways have been implicated in pathogenesis...
December 2016: Clinical Medicine: Journal of the Royal College of Physicians of London
https://www.readbyqxmd.com/read/27942908/could-sirtuin-activities-modify-als-onset-and-progression
#20
REVIEW
Bor Luen Tang
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a complex etiology. Sirtuins have been implicated as disease-modifying factors in several neurological disorders, and in the past decade, attempts have been made to check if manipulating Sirtuin activities and levels could confer benefit in terms of neuroprotection and survival in ALS models. The efforts have largely focused on mutant SOD1, and while limited in scope, the results were largely positive. Here, the body of work linking Sirtuins with ALS is reviewed, with discussions on how Sirtuins and their activities may impact on the major etiological mechanisms of ALS...
December 10, 2016: Cellular and Molecular Neurobiology
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