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C9orf72

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https://www.readbyqxmd.com/read/28431575/heterogeneous-ribonuclear-protein-a3-hnrnp-a3-is-present-in-dipeptide-repeat-protein-containing-inclusions-in-frontotemporal-lobar-degeneration-and-motor-neurone-disease-associated-with-expansions-in-c9orf72-gene
#1
Yvonne S Davidson, Louis Flood, Andrew C Robinson, Yoshihiro Nihei, Kohji Mori, Sara Rollinson, Anna Richardson, Bridget C Benson, Matthew Jones, Julie S Snowden, Stuart Pickering-Brown, Christian Haass, Tammaryn Lashley, David M A Mann
Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those without known mutation...
April 21, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28430856/a-comprehensive-analysis-of-rare-genetic-variation-in-amyotrophic-lateral-sclerosis-in-the-uk
#2
Sarah Morgan, Aleksey Shatunov, William Sproviero, Ashley R Jones, Maryam Shoai, Deborah Hughes, Ahmad Al Khleifat, Andrea Malaspina, Karen E Morrison, Pamela J Shaw, Christopher E Shaw, Katie Sidle, Richard W Orrell, Pietro Fratta, John Hardy, Alan Pittman, Ammar Al-Chalabi
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2...
April 18, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28420437/bidirectional-nucleolar-dysfunction-in-c9orf72-frontotemporal-lobar-degeneration
#3
Sarah Mizielinska, Charlotte E Ridler, Rubika Balendra, Annora Thoeng, Nathan S Woodling, Friedrich A Grässer, Vincent Plagnol, Tammaryn Lashley, Linda Partridge, Adrian M Isaacs
An intronic GGGGCC expansion in C9orf72 is the most common known cause of both frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat expansion leads to the generation of sense and antisense repeat RNA aggregates and dipeptide repeat (DPR) proteins, generated by repeat-associated non-ATG translation. The arginine-rich DPR proteins poly(glycine-arginine or GR) and poly(proline-arginine or PR) are potently neurotoxic and can localise to the nucleolus when expressed in cells, resulting in enlarged nucleoli with disrupted functionality...
April 18, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28420385/frontotemporal-dementia-as-a-comorbidity-to-idiopathic-normal-pressure-hydrocephalus-inph-a-short-review-of-literature-and-an-unusual-case
#4
V E Korhonen, E Solje, N M Suhonen, T Rauramaa, R Vanninen, A M Remes, V Leinonen
Behavioural variant frontotemporal dementia (bvFTD) and idiopathic normal pressure hydrocephalus (iNPH) are neurodegenerative diseases that can present with similar symptoms. These include decline in executive functions, psychomotor slowness, and behavioural and personality changes. Ventricular enlargement is a key radiological finding in iNPH that may also be present in bvFTD caused by the C9ORF72 expansion mutation. Due to this, bvFTD has been hypothesized as a potential comorbidity to iNPH but bvFTD patients have never been identified in studies focusing in clinical comorbidities with iNPH...
April 19, 2017: Fluids and Barriers of the CNS
https://www.readbyqxmd.com/read/28413711/high-throughput-sequencing-revealed-a-novel-setx-mutation-in-a-hungarian-patient-with-amyotrophic-lateral-sclerosis
#5
Kornélia Tripolszki, Dóra Török, David Goudenège, Katalin Farkas, Adrienn Sulák, Nóra Török, József I Engelhardt, Péter Klivényi, Vincent Procaccio, Nikoletta Nagy, Márta Széll
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of the motor neurons. To date, 126 genes have been implicated in ALS. Therefore, the heterogenous genetic background of ALS requires comprehensive genetic investigative approaches. METHODS: In this study, DNA from 28 Hungarian ALS patients was subjected to targeted high-throughput sequencing of the coding regions of three Mendelian ALS genes: FUS, SETX, and C9ORF72...
April 2017: Brain and Behavior
https://www.readbyqxmd.com/read/28409281/spinal-poly-ga-inclusions-in-a-c9orf72-mouse-model-trigger-motor-deficits-and-inflammation-without-neuron-loss
#6
Martin H Schludi, Lore Becker, Lillian Garrett, Tania F Gendron, Qihui Zhou, Franziska Schreiber, Bastian Popper, Leda Dimou, Tim M Strom, Juliane Winkelmann, Anne von Thaden, Kristin Rentzsch, Stephanie May, Meike Michaelsen, Benjamin M Schwenk, Jing Tan, Benedikt Schoser, Marianne Dieterich, Leonard Petrucelli, Sabine M Hölter, Wolfgang Wurst, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Thomas Klopstock, Thomas Arzberger, Dieter Edbauer
Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples...
April 13, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28408402/poly-gp-in-cerebrospinal-fluid-links-c9orf72-associated-dipeptide-repeat-expression-to-the-asymptomatic-phase-of-als-ftd
#7
Carina Lehmer, Patrick Oeckl, Jochen H Weishaupt, Alexander E Volk, Janine Diehl-Schmid, Matthias L Schroeter, Martin Lauer, Johannes Kornhuber, Johannes Levin, Klaus Fassbender, Bernhard Landwehrmeyer, Martin H Schludi, Thomas Arzberger, Elisabeth Kremmer, Andrew Flatley, Regina Feederle, Petra Steinacker, Patrick Weydt, Albert C Ludolph, Dieter Edbauer, Markus Otto
The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non-conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain-of-function mechanism. Here, we established a poly-GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly-GP levels were already detectable in asymptomatic C9orf72 mutation carriers compared to healthy controls and patients with other neurodegenerative diseases...
April 13, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28402699/inhibition-of-retrograde-transport-modulates-misfolded-protein-accumulation-and-clearance-in-motoneuron-diseases
#8
Riccardo Cristofani, Valeria Crippa, Paola Rusmini, Maria Elena Cicardi, Marco Meroni, Nausicaa V Licata, Gessica Sala, Elisa Giorgetti, Christopher Grunseich, Mariarita Galbiati, Margherita Piccolella, Elio Messi, Carlo Ferrarese, Serena Carra, Angelo Poletti
Motoneuron diseases, like spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS), are associated with proteins that because of gene mutation or peculiar structures, acquire aberrant (misfolded) conformations toxic to cells. To prevent misfolded protein toxicity, cells activate a protein quality control (PQC) system composed of chaperones and degradative pathways (proteasome and autophagy). Inefficient activation of the PQC system results in misfolded protein accumulation that ultimately leads to neuronal cell death, while efficient macroautophagy/autophagy-mediated degradation of aggregating proteins is beneficial...
April 12, 2017: Autophagy
https://www.readbyqxmd.com/read/28387671/predicting-development-of-amyotrophic-lateral-sclerosis-in-frontotemporal-dementia
#9
Tim Van Langenhove, Olivier Piguet, James R Burrell, Cristian Leyton, David Foxe, Melissa Abela, Lauren Bartley, Woojin S Kim, Eve Jary, Yue Huang, Carol Dobson-Stone, John B Kwok, Glenda M Halliday, John R Hodges
BACKGROUND: A proportion of patients with frontotemporal dementia (FTD) also develop amyotrophic lateral sclerosis (ALS). OBJECTIVE: We aimed to establish the risk of developing ALS in patients presenting with FTD and to identify the relevant clinical variables associated with progression from FTD to FTD-ALS. METHODS: Of 218 consecutive patients with FTD, 10.1% had a dual FTD-ALS diagnosis at presentation. The remaining 152 FTD patients with follow-up of at least 12 months were included in the present study...
April 3, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28380318/recent-advances-in-the-molecular-genetics-of-frontotemporal-lobar-degeneration
#10
REVIEW
Innocenzo Rainero, E Rubino, A Michelerio, F D'Agata, Salvatore Gentile, Lorenzo Pinessi
The term frontotemporal lobar degeneration (FTLD) describes a spectrum of neurodegenerative disorders associated with deposition of misfolded proteins in the frontal and temporal lobes. Up to 40% of FTLD patients reports a family history of neurodegeneration, and approximately 1/3 of familial cases shows an autosomal dominant pattern of inheritance of the phenotype. Over the past two decades, several causative and susceptibility genes for FTLD have been discovered, supporting the notion that genetic factors are important contributors to the disease processes...
January 2017: Functional Neurology
https://www.readbyqxmd.com/read/28377694/drosophila-melanogaster-as-a-model-organism-to-study-rna-toxicity-of-repeat-expansion-associated-neurodegenerative-and-neuromuscular-diseases
#11
REVIEW
Alex C Koon, Ho Yin Edwin Chan
For nearly a century, the fruit fly, Drosophila melanogaster, has proven to be a valuable tool in our understanding of fundamental biological processes, and has empowered our discoveries, particularly in the field of neuroscience. In recent years, Drosophila has emerged as a model organism for human neurodegenerative and neuromuscular disorders. In this review, we highlight a number of recent studies that utilized the Drosophila model to study repeat-expansion associated diseases (READs), such as polyglutamine diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), myotonic dystrophy type 1 (DM1) and type 2 (DM2), and C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia (C9-ALS/FTD)...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28365006/mutations-in-c19orf12-and-intronic-repeat-expansions-in-c9orf72-not-observed-in-iranian-parkinson-s-disease-patients
#12
Afagh Alavi, Maryam Malakouti Nejad, Gholamali Shahidi, Elahe Elahi
Various neurodegenerative disorders share some clinical features that sometimes renders differential diagnosis challenging. Genetic-based classification also has limitations as mutations in the same gene are sometimes associated with different clinically based diagnoses. In this light, we screened the C19orf12 neurodegeneration with brain iron accumulation (NBIA) causing gene and the C9orf72 intronic expansion mutation that is cause of amyotrophic lateral sclerosis in 186 Iranian Parkinson's disease (PD) patients...
March 18, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28364657/genetic-models-of-c9orf72-what-is-toxic
#13
REVIEW
Thomas G Moens, Linda Partridge, Adrian M Isaacs
A hexanucleotide repeat expansion in the gene C9orf72 is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Pathogenesis may occur either due to loss of function of the C9orf72 gene, or a toxic gain of function, via the production of repetitive sense and antisense RNA and/or repetitive dipeptide repeat proteins. Recently, mouse knockouts have suggested that a loss of function of C9orf72 alone is insufficient to lead to neurodegeneration, whilst overexpression of hexanucleotide DNA is sufficient in a wide range of model systems...
March 29, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28356511/poly-gp-proteins-are-a-useful-pharmacodynamic-marker-for-c9orf72-associated-amyotrophic-lateral-sclerosis
#14
Tania F Gendron, Jeannie Chew, Jeannette N Stankowski, Lindsey R Hayes, Yong-Jie Zhang, Mercedes Prudencio, Yari Carlomagno, Lillian M Daughrity, Karen Jansen-West, Emilie A Perkerson, Aliesha O'Raw, Casey Cook, Luc Pregent, Veronique Belzil, Marka van Blitterswijk, Lilia J Tabassian, Chris W Lee, Mei Yue, Jimei Tong, Yuping Song, Monica Castanedes-Casey, Linda Rousseau, Virginia Phillips, Dennis W Dickson, Rosa Rademakers, John D Fryer, Beth K Rush, Otto Pedraza, Ana M Caputo, Pamela Desaro, Carla Palmucci, Amelia Robertson, Michael G Heckman, Nancy N Diehl, Edythe Wiggs, Michael Tierney, Laura Braun, Jennifer Farren, David Lacomis, Shafeeq Ladha, Christina N Fournier, Leo F McCluskey, Lauren B Elman, Jon B Toledo, Jennifer D McBride, Cinzia Tiloca, Claudia Morelli, Barbara Poletti, Federica Solca, Alessandro Prelle, Joanne Wuu, Jennifer Jockel-Balsarotti, Frank Rigo, Christine Ambrose, Abhishek Datta, Weixing Yang, Denitza Raitcheva, Giovanna Antognetti, Alexander McCampbell, John C Van Swieten, Bruce L Miller, Adam L Boxer, Robert H Brown, Robert Bowser, Timothy M Miller, John Q Trojanowski, Murray Grossman, James D Berry, William T Hu, Antonia Ratti, Bryan J Traynor, Matthew D Disney, Michael Benatar, Vincenzo Silani, Jonathan D Glass, Mary Kay Floeter, Jeffrey D Rothstein, Kevin B Boylan, Leonard Petrucelli
There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated...
March 29, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28351931/antibodies-inhibit-transmission-and-aggregation-of-c9orf72-poly-ga-dipeptide-repeat-proteins
#15
Qihui Zhou, Carina Lehmer, Meike Michaelsen, Kohji Mori, Dominik Alterauge, Dirk Baumjohann, Martin H Schludi, Johanna Greiling, Daniel Farny, Andrew Flatley, Regina Feederle, Stephanie May, Franziska Schreiber, Thomas Arzberger, Christoph Kuhm, Thomas Klopstock, Andreas Hermann, Christian Haass, Dieter Edbauer
Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins...
March 28, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28344074/aberrant-distributions-of-nuclear-pore-complex-proteins-in-als-mice-and-als-patients
#16
Jingwei Shang, Toru Yamashita, Yumiko Nakano, Ryuta Morihara, Xianghong Li, Tian Feng, Xia Liu, Yong Huang, Yusuke Fukui, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe
Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease. In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients...
March 24, 2017: Neuroscience
https://www.readbyqxmd.com/read/28337409/network-degeneration-and-dysfunction-in-presymptomatic-c9orf72-expansion-carriers
#17
Suzee E Lee, Ana C Sias, Maria Luisa Mandelli, Jesse A Brown, Alainna B Brown, Anna M Khazenzon, Anna A Vidovszky, Theodore P Zanto, Anna M Karydas, Mochtar Pribadi, Deepika Dokuru, Giovanni Coppola, Dan H Geschwind, Rosa Rademakers, Maria Luisa Gorno-Tempini, Howard J Rosen, Bruce L Miller, William W Seeley
Hexanucleotide repeat expansions in C9ORF72 are the most common known genetic cause of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis. Previous work has shown that patients with behavioral variant frontotemporal dementia due to C9ORF72 show salience and sensorimotor network disruptions comparable to those seen in sporadic behavioral variant frontotemporal dementia, but it remains unknown how early in the lifespan these and other changes in brain structure and function arise...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28334866/c9orf72-and-rab7l1-regulate-vesicle-trafficking-in-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia
#18
Yoshitsugu Aoki, Raquel Manzano, Yi Lee, Ruxandra Dafinca, Misako Aoki, Andrew G L Douglas, Miguel A Varela, Chaitra Sathyaprakash, Jakub Scaber, Paola Barbagallo, Pieter Vader, Imre Mäger, Kariem Ezzat, Martin R Turner, Naoki Ito, Samanta Gasco, Norihiko Ohbayashi, Samir El Andaloussi, Shin'ichi Takeda, Mitsunori Fukuda, Kevin Talbot, Matthew J A Wood
A non-coding hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), however, the precise molecular mechanism by which the C9orf72 hexanucleotide repeat expansion directs C9ALS/FTD pathogenesis remains unclear. Here, we report a novel disease mechanism arising due to the interaction of C9ORF72 with the RAB7L1 GTPase to regulate vesicle trafficking. Endogenous interaction between C9ORF72 and RAB7L1 was confirmed in human SH-SY5Y neuroblastoma cells...
April 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28325066/comprehensive-analysis-to-explain-reduced-or-increased-sod1-enzymatic-activity-in-als-patients-and-their-relatives
#19
Isil Keskin, Anna Birve, Mariusz Berdynski, Karin Hjertkvist, Reza Rofougaran, Torbjörn K Nilsson, Jonathan D Glass, Stefan L Marklund, Peter M Andersen
OBJECTIVE: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. METHODS: Blood samples from 4072 individuals, ALS patients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed...
March 21, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28320191/c9orf72-hexanucleotide-repeat-expansions-are-not-a-common-cause-of-obsessive-compulsive-disorder
#20
Karissa C Arthur, Alberto M Rivera, Jack Samuels, Ying Wang, Marco Grados, Fernando S Goes, Brion Maher, Gerald Nestadt, Bryan J Traynor
Obsessive-compulsive disorder (OCD) is a polygenic neuropsychiatric disorder characterized by repetitive thoughts and behaviors that cause distress. The pathogenic repeat expansion [GGGGCC]n found at the C9orf72 locus is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and has also been documented in patients with psychosis and schizophrenia. Furthermore, obsessions and compulsions have been identified in patients diagnosed with ALS and/or FTD and carrying the pathogenic repeat expansion...
April 15, 2017: Journal of the Neurological Sciences
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