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C9orf72

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https://www.readbyqxmd.com/read/28637276/repetitive-element-transcripts-are-elevated-in-the-brain-of-c9orf72-als-ftld-patients
#1
Mercedes Prudencio, Patrick K Gonzales, Casey N Cook, Tania F Gendron, Lillian M Daughrity, Yuping Song, Mark T W Ebbert, Marka van Blitterswijk, Yong-Jie Zhang, Karen Jansen-West, Matthew C Baker, Michael DeTure, Rosa Rademakers, Kevin B Boylan, Dennis W Dickson, Leonard Petrucelli, Christopher D Link
Significant transcriptome alterations are detected in the brain of patients with amyotrophic lateral sclerosis (ALS), including carriers of the C9orf72 repeat expansion and C9orf72-negative sporadic cases. Recently, the expression of repetitive element transcripts has been associated with toxicity and, while increased repetitive element expression has been observed in several neurodegenerative diseases, little is known about their contribution to ALS. To assess whether aberrant expression of repetitive element sequences are observed in ALS, we analyzed RNA sequencing data from C9orf72-positive and sporadic ALS cases, as well as healthy controls...
June 16, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28631957/prognostic-value-of-clinical-and-electrodiagnostic-parameters-at-time-of-diagnosis-in-patients-with-amyotrophic-lateral-sclerosis
#2
Wendeline Reniers, Maarten Schrooten, Kristl G Claeys, Petra Tilkin, Ann D'Hondt, Dimphna Van Reijen, Goedele Couwelier, Nikita Lamaire, Wim Robberecht, Steffen Fieuws, Philip Van Damme
OBJECTIVE: To assess the added prognostic value of the aggregated clinical and electrodiagnostic data, which define a given diagnostic category according to the Awaji or revised El Escorial criteria at time of diagnosis in patients with amyotrophic lateral sclerosis (ALS). METHODS: Clinical signs and electrodiagnostic test results were collected at time of diagnosis in 396 patients with ALS between January 2009 and January 2016. Significant predictors of prognosis were identified using a univariate model, and later combined in a multivariate Cox regression model...
February 15, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28628244/phosphorylated-neurofilament-heavy-chain-a-biomarker-of-survival-for-c9orf72-associated-amyotrophic-lateral-sclerosis
#3
Tania F Gendron, Lillian M Daughrity, Michael G Heckman, Nancy N Diehl, Joanne Wuu, Timothy M Miller, Pau Pastor, John Q Trojanowski, Murray Grossman, James D Berry, William T Hu, Antonia Ratti, Michael Benatar, Vincenzo Silani, Jonathan D Glass, Mary Kay Floeter, Andreas Jeromin, Kevin B Boylan, Leonard Petrucelli
As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions...
June 19, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28620717/multiple-variants-in-families-with-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia-related-to-c9orf72-repeat-expansion-further-observations-on-their-oligogenic-nature
#4
Maria Pia Giannoccaro, Anna Bartoletti-Stella, Silvia Piras, Annalisa Pession, Patrizia De Massis, Federico Oppi, Michelangelo Stanzani-Maserati, Elena Pasini, Simone Baiardi, Patrizia Avoni, Piero Parchi, Rocco Liguori, Sabina Capellari
The C9orf72 repeat expansion (RE) is one of the most frequent causative mutations of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it is still unclear how the C9orf72 RE can lead to a heterogeneous phenotype. Several reports have shown the coexistence of mutations in multiple ALS/FTD causative genes in the same family, suggesting an oligogenic etiology for ALS and FTD. Our aim was to investigate this phenomenon in an Italian group of ALS/FTD pedigrees carrying the C9orf72 RE...
June 15, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28615433/disease-progression-in-c9orf72-mutation-carriers
#5
Mary K Floeter, Bryan J Traynor, Jennifer Farren, Laura E Braun, Michael Tierney, Edythe A Wiggs, Tianxia Wu
OBJECTIVE: To assess changes in 3 clinical measures, the Revised ALS Functional Rating Scale (ALSFRS-R), letter fluency, and Frontal Behavioral Inventory (FBI), over time in C9orf72 mutation carriers (C9+) with varied clinical phenotypes. METHODS: Thirty-four unrelated participants with mutations in C9orf72 were enrolled in a prospective natural history study. Participants were classified as asymptomatic, amyotrophic lateral sclerosis (ALS), ALS-familial frontotemporal dementia (FTD), or behavioral-variant FTD by clinical diagnostic criteria...
June 14, 2017: Neurology
https://www.readbyqxmd.com/read/28614712/evidence-that-c9orf72-dipeptide-repeat-proteins-associate-with-u2-snrnp-to-cause-mis-splicing-in-als-ftd-patients
#6
Shanye Yin, Rodrigo Lopez-Gonzalez, Ryan C Kunz, Jaya Gangopadhyay, Carl Borufka, Steven P Gygi, Fen-Biao Gao, Robin Reed
Hexanucleotide repeat expansion in the C9ORF72 gene results in production of dipeptide repeat (DPR) proteins that may disrupt pre-mRNA splicing in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. At present, the mechanisms underlying this mis-splicing are not understood. Here, we show that addition of proline-arginine (PR) and glycine-arginine (GR) toxic DPR peptides to nuclear extracts blocks spliceosome assembly and splicing, but not other types of RNA processing. Proteomic and biochemical analyses identified the U2 small nuclear ribonucleoprotein particle (snRNP) as a major interactor of PR and GR peptides...
June 13, 2017: Cell Reports
https://www.readbyqxmd.com/read/28611593/autophagy-and-its-impact-on-neurodegenerative-diseases-new-roles-for-tdp-43-and-c9orf72
#7
REVIEW
Mauricio Budini, Emanuele Buratti, Eugenia Morselli, Alfredo Criollo
Autophagy is a catabolic mechanism where intracellular material is degraded by vesicular structures called autophagolysosomes. Autophagy is necessary to maintain the normal function of the central nervous system (CNS), avoiding the accumulation of misfolded and aggregated proteins. Consistently, impaired autophagy has been associated with the pathogenesis of various neurodegenerative diseases. The proteins TAR DNA-binding protein-43 (TDP-43), which regulates RNA processing at different levels, and chromosome 9 open reading frame 72 (C9orf72), probably involved in membrane trafficking, are crucial in the development of neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28608264/the-small-heat-shock-protein-b8-hspb8-efficiently-removes-aggregating-species-of-dipeptides-produced-in-c9orf72-related-neurodegenerative-diseases
#8
Riccardo Cristofani, Valeria Crippa, Giulia Vezzoli, Paola Rusmini, Mariarita Galbiati, Maria Elena Cicardi, Marco Meroni, Veronica Ferrari, Barbara Tedesco, Margherita Piccolella, Elio Messi, Serena Carra, Angelo Poletti
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two neurodegenerative diseases in which similar pathogenic mechanisms are involved. Both diseases associate to the high propensity of specific misfolded proteins, like TDP-43 or FUS, to mislocalize and aggregate. This is partly due to their intrinsic biophysical properties and partly as a consequence of failure of the neuronal protein quality control (PQC) system. Several familial ALS/FTD cases are linked to an expansion of a repeated G4C2 hexanucleotide sequence present in the C9ORF72 gene...
June 12, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28606110/a-c9orf72-bac-mouse-model-recapitulates-key-epigenetic-perturbations-of-als-ftd
#9
Rustam Esanov, Gabriela Toro Cabrera, Nadja S Andrade, Tania F Gendron, Robert H Brown, Michael Benatar, Claes Wahlestedt, Christian Mueller, Zane Zeier
BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal and progressive neurodegenerative disorder with identified genetic causes representing a significant minority of all cases. A GGGGCC hexanucleotide repeat expansion (HRE) mutation within the C9ORF72 gene has recently been identified as the most frequent known cause of ALS. The expansion leads to partial heterochromatinization of the locus, yet mutant RNAs and dipeptide repeat proteins (DPRs) are still produced in sufficient quantities to confer neurotoxicity...
June 12, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28585384/modeling-the-c9orf72-repeat-expansion-mutation-using-human-induced-pluripotent-stem-cells
#10
Bhuvaneish T Selvaraj, Matthew R Livesey, Siddharthan Chandran
C9ORF72 repeat expansion is the most frequent causal genetic mutation giving rise to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). The relatively recent discovery of the C9ORF72 repeat expansion in 2011 and the complexity of the mutation have meant that animal models that successfully recapitulate human C9ORF72 repeat expansion-mediated disease are only now emerging. Concurrent advances in the use of patient-derived induced pluripotent stem cells (iPSCs) to model aspects of neurological disease offers an additional approach for the study of C9ORF72 mutation...
July 2017: Brain Pathology
https://www.readbyqxmd.com/read/28573364/-genetic-architecture-of-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia-overlap-and-differences
#11
REVIEW
M Synofzik, M Otto, A Ludolph, J H Weishaupt
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) overlap not only clinically, but also with respect to shared neuropathology and genes. A large number of novel genes has recently been identified which underlie both diseases, e. g., C9orf72, TARDBP, GRN, TBK1, UBQLN2, VCP, CHCHD10, or SQSTM1. In contrast, other genes are still largely associated with only one of the two diseases, e. g., SOD1 with ALS or MAPT with FTD. These genetic findings indicate a large number of shared mechanisms, yet along with still a certain cell-specific vulnerability...
June 1, 2017: Der Nervenarzt
https://www.readbyqxmd.com/read/28570551/assay-to-measure-nucleocytoplasmic-transport-in-real-time-within-motor-neuron-like-nsc-34-cells
#12
Tom Shani, Moshe Levy, Adrian Israelson
Nucleocytoplasmic transport refers to the import and export of large molecules from the cell nucleus. Recently, a number of studies have shown a connection between amyotrophic lateral sclerosis (ALS) and impairments in the nucleocytoplasmic pathway. ALS is a neurodegenerative disease affecting the motor neurons and resulting in paralysis and ultimately in death, within 2-5 years on average. Most cases of ALS are sporadic, lacking any apparent genetic linkage, but 10% are inherited in a dominant manner. Recently, hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 (C9orf72) gene were identified as a genetic cause of ALS and frontotemporal dementia (FTD)...
May 16, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28566149/clinical-profile-of-motor-neuron-disease-patients-with-lower-urinary-tract-symptoms-and-neurogenic-bladder
#13
Juan Francisco Vázquez-Costa, Salvador Arlandis, David Hervas, Esther Martínez-Cuenca, Fernando Cardona, Jordi Pérez-Tur, Enrique Broseta, Teresa Sevilla
INTRODUCTION: Lower urinary tract symptoms (LUTS) are frequent in motor neuron disease (MND) patients, but clinical factors related to them are unknown. We describe differences in LUTS among MND phenotypes and their relationship with other clinical characteristics, including prognosis. METHODS: For this study, we collected clinical data of a previously published cohort of patients diagnosed with classical amyotrophic lateral sclerosis (cALS), progressive muscular atrophy (PMA) or primary lateral sclerosis (PLS) with and without LUTS...
July 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28562080/neuroimaging-patterns-along-the-als-ftd-spectrum-a-multiparametric-imaging-study
#14
Taha Omer, Eoin Finegan, Siobhan Hutchinson, Mark Doherty, Alice Vajda, Russell L McLaughlin, Niall Pender, Orla Hardiman, Peter Bede
Frontotemporal dementia is associated with considerable clinical, genetic and pathological heterogeneity. The objective of this study is to characterise the imaging signatures of the main FTD phenotypes along the ALS-FTD spectrum. A total of 100 participants underwent comprehensive multimodal neuroimaging, genetic testing and neuropsychological evaluation. Seven patients with behavioural variant FTD (bvFTD), 11 patients with non-fluent-variant primary progressive aphasia (nfvPPA), two patients with sematic-variant primary progressive aphasia(svPPA), 10 patients with amyotrophic lateral sclerosis and FTD carrying the C9orf72 hexanucleotide repeat (C9 + ALS-FTD), 10 patients with ALS-FTD without hexanucleotide repeats (C9-ALS-FTD), 20 ALS patients without behavioural or cognitive deficits (ALSnci) and 40 healthy controls (HC) were included in a prospective quantitative neuroimaging study...
May 31, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28562075/c9orf72-mutations-do-not-influence-the-tau-signature-of-amyotrophic-lateral-sclerosis-with-cognitive-impairment-alsci
#15
Kathryn Volkening, Wendy L Strong, Shauntel Seaton, Wencheng Yang, Michael J Strong
OBJECTIVE: C9orf72 mutations are associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD. In addition to ALS-FTD, ALS patients may develop a spectrum of neuropsychological and neuropsychiatric deficits including ALS with cognitive impairment (ALSci). Here we examine the extent to which C9orf72 mutations are associated with ALSci and whether this alters the tau molecular signature. METHODS: We identified 16 ALSci cases within a post-mortem archive of 94 fully genotyped ALS cases, eight of which harboured a C9orf72 mutation, in addition to three cognitively-intact ALS cases with a C9orf72 mutation...
May 31, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28551275/genetic-analysis-of-vcp-and-wash-complex-genes-in-a-german-cohort-of-sporadic-als-ftd-patients
#16
Matthias Türk, Rolf Schröder, Katharina Khuller, Andreas Hofmann, Carolin Berwanger, Albert C Ludolph, Gabriele Dekomien, Kathrin Müller, Jochen H Weishaupt, Christian T Thiel, Christoph S Clemen
Mutations of the human valosin-containing protein, p97 (VCP) and Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex genes cause motor neuron and cognitive impairment disorders. Here, we analyzed a cohort of German patients with sporadic amyotrophic lateral sclerosis and frontotemporal lobar degeneration comorbidity (ALS/FTD) for VCP and WASH complex gene mutations. Next-generation panel sequencing of VCP, WASH1, FAM21C, CCDC53, SWIP, strumpellin, F-actin capping protein of muscle Z-line alfa 1 (CAPZA1), and CAPZB genes was performed in 43 sporadic ALS/FTD patients...
May 3, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28550099/viral-delivery-of-c9orf72-hexanucleotide-repeat-expansions-in-mice-lead-to-repeat-length-dependent-neuropathology-and-behavioral-deficits
#17
Saul Herranz-Martin, Jayanth Chandran, Katherine Lewis, Padraig Mulcahy, Adrian Higginbottom, Callum Walker, Isabel Martinez-Pena Y Valenzuela, Ross A Jones, Ian Coldicott, Tommaso Iannitti, Mohammed Akaaboune, Sherif F El-Khamisy, Thomas H Gillingwater, Pamela J Shaw, Mimoun Azzouz
Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, though it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here we generated two novel lines of mice that overexpress either 10 pure or 102 interrupted G4C2 repeats mediated by adeno-associated virus (AAV) and characterized relevant pathology and disease-related behavioral phenotypes...
May 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28542233/is-survival-improved-by-the-use-of-niv-and-peg-in-amyotrophic-lateral-sclerosis-als-a-post-mortem-study-of-80-als-patients
#18
Christian Burkhardt, Christoph Neuwirth, Andreas Sommacal, Peter M Andersen, Markus Weber
BACKGROUND: Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom management in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the impact on causes of death is unknown. OBJECTIVE: To investigate the effect of NIV and PEG on survival and causes of death in ALS patients. METHODS: Eighty deceased ALS patients underwent a complete post mortem analysis for causes of death between 2003 and 2015...
2017: PloS One
https://www.readbyqxmd.com/read/28539470/the-src-c-abl-pathway-is-a-potential-therapeutic-target-in-amyotrophic-lateral-sclerosis
#19
Keiko Imamura, Yuishin Izumi, Akira Watanabe, Kayoko Tsukita, Knut Woltjen, Takuya Yamamoto, Akitsu Hotta, Takayuki Kondo, Shiho Kitaoka, Akira Ohta, Akito Tanaka, Dai Watanabe, Mitsuya Morita, Hiroshi Takuma, Akira Tamaoka, Tilo Kunath, Selina Wray, Hirokazu Furuya, Takumi Era, Kouki Makioka, Koichi Okamoto, Takao Fujisawa, Hideki Nishitoh, Kengo Homma, Hidenori Ichijo, Jean-Pierre Julien, Nanako Obata, Masato Hosokawa, Haruhiko Akiyama, Satoshi Kaneko, Takashi Ayaki, Hidefumi Ito, Ryuji Kaji, Ryosuke Takahashi, Shinya Yamanaka, Haruhisa Inoue
Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro...
May 24, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28533210/specific-biomarkers-for-c9orf72-ftd-als-could-expedite-the-journey-towards-effective-therapies
#20
Rubika Balendra, Thomas G Moens, Adrian M Isaacs
No abstract text is available yet for this article.
May 22, 2017: EMBO Molecular Medicine
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