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C9orf72

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https://www.readbyqxmd.com/read/29131108/genetic-and-pathological-assessment-of-hnrnpa1-hnrnpa2-b1-and-hnrnpa3-in-familial-and-sporadic-amyotrophic-lateral-sclerosis
#1
Jennifer A Fifita, Katharine Y Zhang, Jasmin Galper, Kelly L Williams, Emily P McCann, Alison L Hogan, Neil Saunders, Denis Bauer, Ingrid S Tarr, Roger Pamphlett, Garth A Nicholson, Dominic Rowe, Shu Yang, Ian P Blair
BACKGROUND: Mutations in the genes encoding the heterogeneous nuclear ribonucleoproteins hnRNPA1 and hnRNPA2/B1 have been reported in a multisystem proteinopathy that includes amyotrophic lateral sclerosis (ALS) and inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia. Mutations were also described in the prion-like domain of hnRNPA1 in patients with classic ALS. Another hnRNP protein, hnRNPA3, has been found to be associated with the ALS/frontotemporal dementia protein C9orf72...
November 11, 2017: Neuro-degenerative Diseases
https://www.readbyqxmd.com/read/29128563/matrin-3-is-a-component-of-neuronal-cytoplasmic-inclusions-of-motor-neurons-in-sporadic-amyotrophic-lateral-sclerosis
#2
Mikiko Tada, Hiroshi Doi, Shigeru Koyano, Shun Kubota, Ryoko Fukai, Shunta Hashiguchi, Noriko Hayashi, Yuko Kawamoto, Misako Kunii, Kenichi Tanaka, Keita Takahashi, Yuki Ogawa, Ryo Iwata, Shoji Yamanaka, Hideyuki Takeuchi, Fumiaki Tanaka
Mutations in the matrin 3 (MATR3) gene have been identified as a cause of familial amyotrophic lateral sclerosis, but the involvement of MATR3 protein in sporadic amyotrophic lateral sclerosis (SALS) pathology has not been fully assessed. Here, we immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsies. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns, mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases...
November 8, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/29113975/g-quadruplex-binding-small-molecules-ameliorate-c9orf72-ftd-als-pathology-in%C3%A2-vitro-and-in%C3%A2-vivo
#3
Roberto Simone, Rubika Balendra, Thomas G Moens, Elisavet Preza, Katherine M Wilson, Amanda Heslegrave, Nathan S Woodling, Teresa Niccoli, Javier Gilbert-Jaramillo, Samir Abdelkarim, Emma L Clayton, Mica Clarke, Marie-Therese Konrad, Andrew J Nicoll, Jamie S Mitchell, Andrea Calvo, Adriano Chio, Henry Houlden, James M Polke, Mohamed A Ismail, Chad E Stephens, Tam Vo, Abdelbasset A Farahat, W David Wilson, David W Boykin, Henrik Zetterberg, Linda Partridge, Selina Wray, Gary Parkinson, Stephen Neidle, Rickie Patani, Pietro Fratta, Adrian M Isaacs
Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA-binding proteins and through toxic dipeptide repeat proteins generated by repeat-associated non-ATG translation. GGGGCC repeat RNA folds into a G-quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy...
November 7, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29102476/investigating-ccnf-mutations-in-a-taiwanese-cohort-with-amyotrophic-lateral-sclerosis
#4
Pei-Chien Tsai, Yi-Chu Liao, Po-Lin Chen, Yuh-Cherng Guo, Ying-Hao Chen, Kang-Yang Jih, Kon-Ping Lin, Bing-Wen Soong, Ching-Paio Tsai, Yi-Chung Lee
Mutations in the cyclin F gene (CCNF) have been recently identified in a small number of patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia, and their role in patients with ALS in Taiwan remains elusive. The aim of this study was to elucidate the frequency and spectrum of CCNF mutations in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of the CCNF gene were performed using Sanger sequencing in a cohort of 255 unrelated patients with ALS. Among these patients, the genetic diagnoses of 204 patients remained unclear after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, HNRNPA2B1, MATR3, CHCHD10, TUBA4A, and TKB1 had been investigated...
October 9, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29095328/c9orf72-intermediate-repeat-expansion-in-a-patient-with-psychiatric-disorders-and-progressive-cerebellar-ataxia
#5
Mario Meloni, Rita Farris, Paolo Solla, Marcello M Mascia, Francesco Marrosu, Antonino Cannas
INTRODUCTION: Large expansions of the noncoding GGGGCC repeat (more than 30) in the first intron of the C9ORF72 gene have been demonstrated to cause amyotrophic lateral sclerosis and frontotemporal dementia. Recent papers have investigated the possible pathogenic role and associated clinical phenotypes of hexanucleotide expansions with intermediate repeat lengths ranging between 20 and 29 repeats. CASE REPORT: We report a case of a 71-year-old Sardinian female patient with a long history of psychiatric disorders such as mixed anxiety-depressive disorder associated with somatization disorder and histrionic personality who developed a slowly progressive cerebellar syndrome, mild cognitive impairment, pyramidal signs, and rapid eye movement sleep behavior disorder with imaging abnormalities on the DaTSCAN single-photon emission computed tomography indicating an alteration in the presynaptic dopaminergic system...
November 2017: Neurologist
https://www.readbyqxmd.com/read/29082510/brain-signal-intensity-changes-as-biomarkers-in-amyotrophic-lateral-sclerosis
#6
Juan F Vázquez-Costa, Miguel Mazón, Joan Carreres-Polo, David Hervás, Jordi Pérez-Tur, Luis Martí-Bonmatí, Teresa Sevilla
OBJECTIVES: To evaluate the contribution of the demographical, clinical, analytical and genetic factors to brain signal intensity changes in T2-weighted MR images in amyotrophic lateral sclerosis (ALS) patients and controls. METHODS: Susceptibility-weighted and FLAIR sequences were obtained in a 3T MR scanner. Iron-related hypointensities in the motor cortex (IRhMC) and hyperintensities of the corticospinal tract (HCT) were qualitatively scored. Age, gender, family history and clinical variables were recorded...
October 29, 2017: Acta Neurologica Scandinavica
https://www.readbyqxmd.com/read/29080331/optn-p-met468arg-and-atxn2-intermediate-length-polyq-extension-in-families-with-c9orf72-mediated-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia
#7
Sali M K Farhan, Tania F Gendron, Leonard Petrucelli, Robert A Hegele, Michael J Strong
We have ascertained two families affected with familial amyotrophic lateral sclerosis (ALS) in which they both carry a hexanucleotide repeat expansion in the C9orf72 gene, specifically in individuals who also presented with frontotemporal dementia (FTD) or behavioral variant FTD (bvFTD). While some reports attribute this phenotypic heterogeneity to the C9orf72 expansion alone, we screened for additional genetic variation in known ALS-FTD genes that may also contribute to or modify the phenotypes. We performed genetic testing consisting of C9orf72 hexanucleotide expansion, ATXN2 polyglutamine (polyQ) expansion, and targeted next generation sequencing using the ONDRISeq, a gene panel consisting of 80 genes known to be associated with neurodegenerative diseases such as ALS, FTD, Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment...
October 28, 2017: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
https://www.readbyqxmd.com/read/29065921/fibroblast-bioenergetics-to-classify-amyotrophic-lateral-sclerosis-patients
#8
Csaba Konrad, Hibiki Kawamata, Kirsten G Bredvik, Andrea J Arreguin, Steven A Cajamarca, Jonathan C Hupf, John M Ravits, Timothy M Miller, Nicholas J Maragakis, Chadwick M Hales, Jonathan D Glass, Steven Gross, Hiroshi Mitsumoto, Giovanni Manfredi
BACKGROUND: The objective of this study was to investigate cellular bioenergetics in primary skin fibroblasts derived from patients with amyotrophic lateral sclerosis (ALS) and to determine if they can be used as classifiers for patient stratification. METHODS: We assembled a collection of unprecedented size of fibroblasts from patients with sporadic ALS (sALS, n = 171), primary lateral sclerosis (PLS, n = 34), ALS/PLS with C9orf72 mutations (n = 13), and healthy controls (n = 91)...
October 24, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29056323/impeding-transcription-of-expanded-microsatellite-repeats-by-deactivated-cas9
#9
Belinda S Pinto, Tanvi Saxena, Ruan Oliveira, Héctor R Méndez-Gómez, John D Cleary, Lance T Denes, Ona McConnell, Juan Arboleda, Guangbin Xia, Maurice S Swanson, Eric T Wang
Transcription of expanded microsatellite repeats is associated with multiple human diseases, including myotonic dystrophy, Fuchs endothelial corneal dystrophy, and C9orf72-ALS/FTD. Reducing production of RNA and proteins arising from these expanded loci holds therapeutic benefit. Here, we tested the hypothesis that deactivated Cas9 enzyme impedes transcription across expanded microsatellites. We observed a repeat length-, PAM-, and strand-dependent reduction of repeat-containing RNAs upon targeting dCas9 directly to repeat sequences; targeting the non-template strand was more effective...
November 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29055436/brain-white-matter-demyelinating-lesions-and-amyotrophic-lateral-sclerosis-in-a-patient-with-c9orf72-hexanucleotide-repeat-expansion
#10
Miguel Oliveira Santos, Inês Caldeira, Marta Gromicho, Ana Pronto-Laborinho, Mamede de Carvalho
A hexanucleotide repeat expansion in the C9orf72 gene is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. It has been described before four patients with multiple sclerosis (MS) and C9orf72-ALS. However, C9orf72 positivity is not associated with increased risk of MS. Inflammatory pathways related to NF-κB have been linked to ALS and MS, and appear to be important in C9orf72-ALS patients. A 42-year-old woman presented with progressive bulbar symptoms for 9 months. Neurological examination disclosed spastic dysarthria, atrophic tongue with fasciculations, brisk jaw and limb tendon reflexes, and bilateral Hoffman sign...
October 2017: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/29054918/non-invasive-in-vivo-neuropathology-of-the-c9orf72-related-als-ftd-syndrome
#11
EDITORIAL
Martin R Turner
No abstract text is available yet for this article.
October 20, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/29054917/longitudinal-diffusion-imaging-across-the-c9orf72-clinical-spectrum
#12
Mary Kay Floeter, Laura E Danielian, Laura E Braun, Tianxia Wu
INTRODUCTION: Discrepancies between diffusion tensor imaging (DTI) findings and functional rating scales in amyotrophic lateral sclerosis (ALS) may be due to symptom heterogeneity, particularly coexisting cognitive-behavioural dysfunction affecting non-motor regions of the brain. Carriers of expansion mutations in the C9orf72 gene, whose motor and cognitive-behavioural symptoms span a range from ALS to frontotemporal dementia, present an opportunity to evaluate the relationship between symptom heterogeneity and DTI changes...
October 20, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/29049464/clustering-of-neuropsychiatric-disease-in-first-degree-and-second-degree-relatives-of-patients-with-amyotrophic-lateral-sclerosis
#13
Margaret O'Brien, Tom Burke, Mark Heverin, Alice Vajda, Russell McLaughlin, John Gibbons, Susan Byrne, Marta Pinto-Grau, Marwa Elamin, Niall Pender, Orla Hardiman
Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition primarily involving the motor system. There is increasing epidemiologic evidence of an association between ALS and a wider spectrum of neurodegenerative and neuropsychiatric disorders among family members, including schizophrenia and psychotic illness and suicidal behavior. Objective: To examine the frequency and range of neuropsychiatric conditions that occur within individual first-degree and second-degree relatives of patients with ALS...
October 16, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/29036691/nuclear-localized-c9orf72-associated-arginine-containing-dipeptides-exhibit-age-dependent-toxicity-in-c-elegans
#14
Paige Rudich, Carley Snoznik, Simon C Watkins, John Monaghan, Udai Bhan Pandey, Todd Lamitina
A hexanucleotide repeat expansion mutation in the C9orf72 gene represents a prevalent genetic cause of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Non-canonical translation of this repeat gives rise to several distinct dipeptide protein species that could play pathological roles in disease. Here, we show in the model system C. elegans that expression of the arginine-containing dipeptides, but not alanine-containing dipeptides, produces toxic phenotypes in multiple cellular contexts, including motor neurons...
September 27, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29035885/als-related-mutant-fus-protein-is-mislocalized-to-cytoplasm-and-is-recruited-into-stress-granules-of-fibroblasts-from-asymptomatic-fus-p525l-mutation-carriers
#15
Margherita Lo Bello, Francesca Di Fini, Antonietta Notaro, Rossella Spataro, Francesca L Conforti, Vincenzo La Bella
BACKGROUND: Amyotrophic lateral sclerosis (ALS) shows a strong genetic basis, with SOD1, FUS, TARDBP, and C9ORF72 being the genes most frequently involved. This has allowed identification of asymptomatic mutation carriers, which may be of help in understanding the molecular changes preceding disease onset. OBJECTIVES: We studied the cellular expression of FUS protein and the effect of heat-shock- and dithiothreitol-induced stress in fibroblasts from FUS P525L mutation carriers, healthy controls, and patients with sporadic ALS...
October 17, 2017: Neuro-degenerative Diseases
https://www.readbyqxmd.com/read/29031901/als-and-ftd-insights-into-the-disease-mechanisms-and-therapeutic-targets
#16
Rajka M Liscic
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The causes are still largely unknown and no effective treatment currently exists. It has been shown that FTLD may coexist with ALS. The overlap between ALS and frontotemporal dementia (FTD), the clinical syndrome associated with FTLD, occurs at clinical, genetic, and pathological levels. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43 or FUS, rarely the disease is caused by mutations in the respective genes...
October 11, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29020091/a-novel-network-analysis-approach-reveals-dna-damage-oxidative-stress-and-calcium-camp-homeostasis-associated-biomarkers-in-frontotemporal-dementia
#17
Fernando Palluzzi, Raffaele Ferrari, Francesca Graziano, Valeria Novelli, Giacomina Rossi, Daniela Galimberti, Innocenzo Rainero, Luisa Benussi, Benedetta Nacmias, Amalia C Bruni, Daniele Cusi, Erika Salvi, Barbara Borroni, Mario Grassi
Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer's disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration...
2017: PloS One
https://www.readbyqxmd.com/read/28990425/mendelian-forms-of-disease-and-age-at-onset-affect-survival-in-frontotemporal-dementia
#18
Maura Cosseddu, Alberto Benussi, Stefano Gazzina, Rosanna Turrone, Silvana Archetti, Elisa Bonomi, Giorgio Biasiotto, Isabella Zanella, Raffaele Ferrari, Maria S Cotelli, Antonella Alberici, Alessandro Padovani, Barbara Borroni
OBJECTIVE: Frontotemporal dementia (FTD) is a common cause of young onset dementia. Very few reports on disease duration are currently available and predictors of survival are still undefined. The aim of the present study was to assess the natural history of FTD and to define predictors of survival. METHODS: Four hundred amd eleven FTD patients, including 294 with behavioural variant FTD, 77 with agrammatic variant primary progressive aphasia (PPA) and 40 with semantic variant PPA, were consecutively enrolled and demographic and clinical variables carefully recorded...
October 8, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28987183/amyotrophic-lateral-sclerosis-and-non-tau-frontotemporal-lobar-degeneration
#19
Tibor Hortobágyi, Nigel J Cairns
Amyotrophic lateral sclerosis (ALS) is the major motor neuron disorder. The hallmark features are progressive, irreversible motor neuron loss leading to denervation atrophy of muscles and death, usually within 5 years of disease onset. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43, or FUS; rarely the disease is caused by mutation of the respective genes. Frontotemporal lobar degeneration (FTLD) is genetically, neuropathologically, and clinically heterogeneous and may present as a dementia with three major clinical syndromes dominated by behavioral, language, and motor disorders, respectively...
2017: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/28980860/the-roles-of-intrinsic-disorder-based-liquid-liquid-phase-transitions-in-the-dr-jekyll-mr-hyde-behavior-of-proteins-involved-in-amyotrophic-lateral-sclerosis-and-frontotemporal-lobar-degeneration
#20
Vladimir N Uversky
Pathological developments leading to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are associated with misbehavior of several key proteins, such as SOD1 (superoxide dismutase 1), TARDBP/TDP-43, FUS, C9orf72, and dipeptide repeat proteins generated as a result of the translation of the intronic hexanucleotide expansions in the C9orf72 gene, PFN1 (profilin 1), GLE1 (GLE1, RNA export mediator), PURA (purine rich element binding protein A), FLCN (folliculin), RBM45 (RNA binding motif protein 45), SS18L1/CREST, HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), ATXN2 (ataxin 2), MAPT (microtubule associated protein tau), and TIA1 (TIA1 cytotoxic granule associated RNA binding protein)...
October 5, 2017: Autophagy
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