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https://www.readbyqxmd.com/read/29777184/genotype-phenotype-links-in-frontotemporal-lobar-degeneration
#1
REVIEW
Sara Van Mossevelde, Sebastiaan Engelborghs, Julie van der Zee, Christine Van Broeckhoven
Frontotemporal lobar degeneration (FTLD) represents a group of neurodegenerative brain diseases with highly heterogeneous clinical, neuropathological and genetic characteristics. This high degree of heterogeneity results from the presence of several different underlying molecular disease processes; consequently, it is unlikely that all patients with FTLD will benefit from a single therapy. Therapeutic strategies for FTLD are currently being explored, and tools are urgently needed that enable the selection of patients who are the most likely to benefit from a particular therapy...
May 18, 2018: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/29772202/rnp-granule-assembly-via-ataxin-2-disordered-domains-is-required-for-long-term-memory-and-neurodegeneration
#2
Baskar Bakthavachalu, Joern Huelsmeier, Indulekha P Sudhakaran, Jens Hillebrand, Amanjot Singh, Arnas Petrauskas, Devasena Thiagarajan, M Sankaranarayanan, Laura Mizoue, Eric N Anderson, Udai Bhan Pandey, Eric Ross, K VijayRaghavan, Roy Parker, Mani Ramaswami
Human Ataxin-2 is implicated in the cause and progression of amyotrophic lateral sclerosis (ALS) and type 2 spinocerebellar ataxia (SCA-2). In Drosophila, a conserved atx2 gene is essential for animal survival as well as for normal RNP-granule assembly, translational control, and long-term habituation. Like its human homolog, Drosophila Ataxin-2 (Atx2) contains polyQ repeats and additional intrinsically disordered regions (IDRs). We demonstrate that Atx2 IDRs, which are capable of mediating liquid-liquid phase transitions in vitro, are essential for efficient formation of neuronal mRNP assemblies in vivo...
May 16, 2018: Neuron
https://www.readbyqxmd.com/read/29761121/poly-gp-neurofilament-and-grey-matter-deficits-in-c9orf72-expansion-carriers
#3
Lieke H H Meeter, Tania F Gendron, Ana C Sias, Lize C Jiskoot, Silvia P Russo, Laura Donker Kaat, Janne M Papma, Jessica L Panman, Emma L van der Ende, Elise G Dopper, Sanne Franzen, Caroline Graff, Adam L Boxer, Howard J Rosen, Raquel Sanchez-Valle, Daniela Galimberti, Yolande A L Pijnenburg, Luisa Benussi, Roberta Ghidoni, Barbara Borroni, Robert Laforce, Marta Del Campo, Charlotte E Teunissen, Rick van Minkelen, Julio C Rojas, Giovanni Coppola, Dan H Geschwind, Rosa Rademakers, Anna M Karydas, Linn Öijerstedt, Elio Scarpini, Giuliano Binetti, Alessandro Padovani, David M Cash, Katrina M Dick, Martina Bocchetta, Bruce L Miller, Jonathan D Rohrer, Leonard Petrucelli, John C van Swieten, Suzee E Lee
Objective: To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72- associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume. Methods: We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers...
May 2018: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29760288/-neuropathologic-subtypes-of-frontotemporal-lobar-degeneration
#4
Mari Tada, Akiyoshi Kakita
Frontotemporal lobar degeneration (FTLD) is a heterogeneous disease entity encompassing a wide variety of histopathological features and genetic backgrounds. The last two decades have seen the discovery of causative genes and the identification of relevant proteins. The current histopathological classification is based on the major types of protein deposition in the brain, and most FTLD cases can be placed into one of three pathological subgroups: FTLD-tau, FTLD-TDP, and FTLD-FUS. Further sub-classification within each subgroup is based on the morphology of neuronal and glial inclusions and lesion distribution...
May 2018: Brain and Nerve, Shinkei Kenkyū No Shinpo
https://www.readbyqxmd.com/read/29750243/c9orf72-dipeptide-repeat-poly-ga-inclusions-promote-intracellular-aggregation-of-phosphorylated-tdp-43
#5
Takashi Nonaka, Masami Masuda-Suzukake, Masato Hosokawa, Aki Shimozawa, Shinobu Hirai, Haruo Okado, Masato Hasegawa
Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are neurodegenerative diseases characterized by accumulation of insoluble aggregates of phosphorylated 43-kDa TAR DNA-binding protein (TDP-43), and linked with abnormal expansion of a hexanucleotide repeat in an intron of chromosome 9 open reading frame 72 (C9ORF72). However, the relationship between C9ORF72 mutations and TDP-43 aggregation remains unknown. Non-ATG-dependent translation of C9ORF72 repeats produces dipeptide repeat (DPR) proteins, which form p62-positive aggregates in cerebral cortex and cerebellum of patients...
May 10, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29748150/targeted-exome-sequencing-reveals-homozygous-trem2-r47c-mutation-presenting-with-behavioral-variant-frontotemporal-dementia-without-bone-involvement
#6
Adeline Sl Ng, Yi Jayne Tan, Zhao Yi, Moses Tandiono, Elaine Chew, Jacqueline Dominguez, Mabel Macas, Ebonne Ng, Shahul Hameed, Simon Ting, Eng King Tan, Jia Nee Foo, Nagaendran Kandiah
To identify genes associated with frontotemporal dementia (FTD) in South-East Asia, targeted exome sequencing and C9orf72 genotyping was performed in 198 subjects (52 patients with FTD and 146 healthy controls) who were screened for mutations in 12 FTD-associated genes. We detected a homozygous TREM2 R47C mutation in a patient with behavioral variant FTD without bone cysts or bone-associated phenotype. Two novel nonsense GRN mutations in 3 FTD patients from the Philippines were detected, but no known pathogenic mutations in other FTD-associated genes were found...
April 16, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29738460/patient-derived-ipscs-and-ins-shedding-new-light-on-the-cellular-etiology-of-neurodegenerative-diseases
#7
Bor Luen Tang
Induced pluripotent stem cells (iPSCs) and induced neuronal (iN) cells are very much touted in terms of their potential promises in therapeutics. However, from a more fundamental perspective, iPSCs and iNs are invaluable tools for the postnatal generation of specific diseased cell types from patients, which may offer insights into disease etiology that are otherwise unobtainable with available animal or human proxies. There are two good recent examples of such important insights with diseased neurons derived via either the iPSC or iN approaches...
May 8, 2018: Cells
https://www.readbyqxmd.com/read/29731301/a-c9orf72-als-ftd-ortholog-acts-in-endolysosomal-degradation-and-lysosomal-homeostasis
#8
Anna Corrionero, H Robert Horvitz
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the expansion of a hexanucleotide repeat in a non-coding region of the gene C9orf72. We report that loss-of-function mutations in alfa-1, the Caenorhabditis elegans ortholog of C9orf72, cause a novel phenotypic defect: endocytosed yolk is abnormally released into the extra-embryonic space, resulting in refractile "blobs." The alfa-1 blob phenotype is partially rescued by the expression of the human C9orf72 protein, demonstrating that C9orf72 and alfa-1 function similarly...
April 24, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29729808/insights-into-c9orf72-related-als-ftd-from-drosophila-and-ipsc-models
#9
REVIEW
Yeliz Yuva-Aydemir, Sandra Almeida, Fen-Biao Gao
GGGGCC (G4 C2 ) repeat expansion in C9ORF72 is the most common genetic cause of ALS and FTD. An important issue is how repeat RNAs and their translation products, various dipeptide repeat (DPR) proteins, cause neurodegeneration. Drosophila has been widely used to model G4 C2 repeat RNA and DPR protein toxicity. Overexpression of disease molecules in flies has revealed important molecular insights. These have been validated and further explored in human neurons differentiated from induced pluripotent stem cells (iPSCs), a disease-relevant model in which expanded G4 C2 repeats are expressed in their native molecular context...
May 2, 2018: Trends in Neurosciences
https://www.readbyqxmd.com/read/29704893/the-behavioural-variant-frontotemporal-dementia-phenocopy-syndrome-is-a-distinct-entity-evidence-from-a-longitudinal-study
#10
E Devenney, T Swinn, E Mioshi, M Hornberger, K E Dawson, S Mead, J B Rowe, J R Hodges
BACKGROUND: This study aimed to i) examine the frequency of C9orf72 expansions in a cohort of patients with the behavioural variant frontotemporal dementia (bvFTD) phenocopy syndrome, ii) observe outcomes in a group of phenocopy syndrome with very long term follow-up and iii) compare progression in a cohort of patients with the phenocopy syndrome to a cohort of patients with probable bvFTD. METHODS: Blood was obtained from 16 phenocopy cases. All met criteria for possible bvFTD and were labeled as phenocopy cases if they showed no functional decline, normal cognitive performance on the Addenbrooke's Cognitive Examination-Revised (ACE-R) and a lack of atrophy on brain imaging, over at least 3 years of follow-up...
April 28, 2018: BMC Neurology
https://www.readbyqxmd.com/read/29685899/multicentre-cross-cultural-population-based-case-control-study-of-physical-activity-as-risk-factor-for-amyotrophic-lateral-sclerosis
#11
Anne E Visser, James P K Rooney, Fabrizio D'Ovidio, Henk-Jan Westeneng, Roel C H Vermeulen, Ettore Beghi, Adriano Chiò, Giancarlo Logroscino, Orla Hardiman, Jan H Veldink, Leonard H van den Berg
OBJECTIVE: To investigate the association between physical activity (PA) and amyotrophic lateral sclerosis (ALS) in population-based case-control studies in three European countries using a validated and harmonised questionnaire. METHODS: Patients with incident ALS and controls were recruited from five population-based registers in The Netherlands, Ireland and Italy. Demographic and data regarding educational level, smoking, alcohol habits and lifetime PA levels in both leisure and work time were gathered by questionnaire, and quantified using metabolic equivalent of task scores...
April 23, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/29650794/comprehensive-analysis-of-the-mutation-spectrum-in-301-german-als-families
#12
Kathrin Müller, David Brenner, Patrick Weydt, Thomas Meyer, Torsten Grehl, Susanne Petri, Julian Grosskreutz, Joachim Schuster, Alexander E Volk, Guntram Borck, Christian Kubisch, Thomas Klopstock, Daniel Zeller, Sibylle Jablonka, Michael Sendtner, Stephan Klebe, Antje Knehr, Kornelia Günther, Joachim Weis, Kristl G Claeys, Berthold Schrank, Anne-Dorte Sperfeld, Annemarie Hübers, Markus Otto, Johannes Dorst, Thomas Meitinger, Tim M Strom, Peter M Andersen, Albert C Ludolph, Jochen H Weishaupt
OBJECTIVES: Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions. METHODS: Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS...
April 12, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/29628143/stress-granule-assembly-disrupts-nucleocytoplasmic-transport
#13
Ke Zhang, J Gavin Daigle, Kathleen M Cunningham, Alyssa N Coyne, Kai Ruan, Jonathan C Grima, Kelly E Bowen, Harsh Wadhwa, Peiguo Yang, Frank Rigo, J Paul Taylor, Aaron D Gitler, Jeffrey D Rothstein, Thomas E Lloyd
Defects in nucleocytoplasmic transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, nucleocytoplasmic transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts nucleocytoplasmic transport. Here, we show that cellular stress disrupts nucleocytoplasmic transport by localizing critical nucleocytoplasmic transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis...
April 2, 2018: Cell
https://www.readbyqxmd.com/read/29610297/intron-retention-induced-by-microsatellite-expansions-as-a-disease-biomarker
#14
Łukasz J Sznajder, James D Thomas, Ellie M Carrell, Tammy Reid, Karen N McFarland, John D Cleary, Ruan Oliveira, Curtis A Nutter, Kirti Bhatt, Krzysztof Sobczak, Tetsuo Ashizawa, Charles A Thornton, Laura P W Ranum, Maurice S Swanson
Expansions of simple sequence repeats, or microsatellites, have been linked to ∼30 neurological-neuromuscular diseases. While these expansions occur in coding and noncoding regions, microsatellite sequence and repeat length diversity is more prominent in introns with eight different trinucleotide to hexanucleotide repeats, causing hereditary diseases such as myotonic dystrophy type 2 (DM2), Fuchs endothelial corneal dystrophy (FECD), and C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD)...
April 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29606954/automatic-mri-quantifying-methods-in-behavioral-variant-frontotemporal-dementia-diagnosis
#15
Antti Cajanus, Anette Hall, Juha Koikkalainen, Eino Solje, Antti Tolonen, Timo Urhemaa, Yawu Liu, Ramona M Haanpää, Päivi Hartikainen, Seppo Helisalmi, Ville Korhonen, Daniel Rueckert, Steen Hasselbalch, Gunhild Waldemar, Patrizia Mecocci, Ritva Vanninen, Mark van Gils, Hilkka Soininen, Jyrki Lötjönen, Anne M Remes
Aims: We assessed the value of automated MRI quantification methods in the differential diagnosis of behavioral-variant frontotemporal dementia (bvFTD) from Alzheimer disease (AD), Lewy body dementia (LBD), and subjective memory complaints (SMC). We also examined the role of the C9ORF72 -related genetic status in the differentiation sensitivity. Methods: The MRI scans of 50 patients with bvFTD (17 C9ORF72 expansion carriers) were analyzed using 6 quantification methods as follows: voxel-based morphometry (VBM), tensor-based morphometry, volumetry (VOL), manifold learning, grading, and white-matter hyperintensities...
January 2018: Dementia and Geriatric Cognitive Disorders Extra
https://www.readbyqxmd.com/read/29599716/atrophy-in-the-thalamus-but-not-cerebellum-is-specific-for-c9orf72-ftd-and-als-patients-an-atlas-based-volumetric-mri-study
#16
Sonja Schönecker, Christiane Neuhofer, Markus Otto, Albert Ludolph, Jan Kassubek, Bernhard Landwehrmeyer, Sarah Anderl-Straub, Elisa Semler, Janine Diehl-Schmid, Catharina Prix, Christian Vollmar, Juan Fortea, Hans-Jürgen Huppertz, Thomas Arzberger, Dieter Edbauer, Berend Feddersen, Marianne Dieterich, Matthias L Schroeter, Alexander E Volk, Klaus Fließbach, Anja Schneider, Johannes Kornhuber, Manuel Maler, Johannes Prudlo, Holger Jahn, Tobias Boeckh-Behrens, Adrian Danek, Thomas Klopstock, Johannes Levin
Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29598923/prognosis-for-patients-with-amyotrophic-lateral-sclerosis-development-and-validation-of-a-personalised-prediction-model
#17
Henk-Jan Westeneng, Thomas P A Debray, Anne E Visser, Ruben P A van Eijk, James P K Rooney, Andrea Calvo, Sarah Martin, Christopher J McDermott, Alexander G Thompson, Susana Pinto, Xenia Kobeleva, Angela Rosenbohm, Beatrice Stubendorff, Helma Sommer, Bas M Middelkoop, Annelot M Dekker, Joke J F A van Vugt, Wouter van Rheenen, Alice Vajda, Mark Heverin, Mbombe Kazoka, Hannah Hollinger, Marta Gromicho, Sonja Körner, Thomas M Ringer, Annekathrin Rödiger, Anne Gunkel, Christopher E Shaw, Annelien L Bredenoord, Michael A van Es, Philippe Corcia, Philippe Couratier, Markus Weber, Julian Grosskreutz, Albert C Ludolph, Susanne Petri, Mamede de Carvalho, Philip Van Damme, Kevin Talbot, Martin R Turner, Pamela J Shaw, Ammar Al-Chalabi, Adriano Chiò, Orla Hardiman, Karel G M Moons, Jan H Veldink, Leonard H van den Berg
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS. METHODS: We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK...
March 26, 2018: Lancet Neurology
https://www.readbyqxmd.com/read/29578490/frontotemporal-dementia-and-chorea-associated-with-a-compound-heterozygous-trem2-mutation
#18
Veronica Redaelli, Ettore Salsano, Lara Colleoni, Paola Corbetta, Giovanni Tringali, Angelo Del Sole, Giorgio Giaccone, Giacomina Rossi
Frontotemporal dementia (FTD) is clinically characterized by behavioral changes, language impairment, and executive dysfunction. FTD usually belongs to the frontotemporal lobar degeneration (FTLD) disease group, and its familial forms are dominantly inherited and linked to a group of genes relevant to frontal and temporal brain pathology, such as MAPT, GRN, C9ORF72, TARDBP, CHMP2B, VCP, and FUS. However, FTD can also be associated with different clinical or pathological phenotypes caused by mutations in other genes, whose heredity can be dominant or recessive...
March 23, 2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29559004/diagnostic-value-of-cerebrospinal-fluid-tau-neurofilament-and-progranulin-in-definite-frontotemporal-lobar-degeneration
#19
Joery Goossens, Maria Bjerke, Sara Van Mossevelde, Tobi Van den Bossche, Johan Goeman, Bart De Vil, Anne Sieben, Jean-Jacques Martin, Patrick Cras, Peter Paul De Deyn, Christine Van Broeckhoven, Julie van der Zee, Sebastiaan Engelborghs
BACKGROUND: We explored the diagnostic performance of cerebrospinal fluid (CSF) biomarkers in allowing differentiation between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD), as well as between FTLD pathological subtypes. METHODS: CSF levels of routine AD biomarkers (phosphorylated tau (p-tau181 ), total tau (t-tau), and amyloid-beta (Aβ)1-42 ) and neurofilament proteins, as well as progranulin levels in both CSF and serum were quantified in definite FTLD (n = 46), clinical AD (n = 45), and cognitively healthy controls (n = 20)...
March 20, 2018: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/29557356/dna-plasticity-and-damage-in-amyotrophic-lateral-sclerosis
#20
REVIEW
Diane Penndorf, Otto W Witte, Alexandra Kretz
The pathophysiology of amyotrophic lateral sclerosis (ALS) is particularly challenging due to the heterogeneity of its clinical presentation and the diversity of cellular, molecular and genetic peculiarities involved. Molecular insights unveiled several novel genetic factors to be inherent in both familial and sporadic disease entities, whose characterizations in terms of phenotype prediction, pathophysiological impact and putative prognostic value are a topic of current researches. However, apart from genetically well-defined high-confidence and other susceptibility loci, the role of DNA damage and repair strategies of the genome as a whole, either elicited as a direct consequence of the underlying genetic mutation or seen as an autonomous parameter, in the initiation and progression of ALS, and the different cues involved in either process are still incompletely understood...
February 2018: Neural Regeneration Research
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