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https://www.readbyqxmd.com/read/28717666/whole-exome-sequencing-and-dna-methylation-analysis-in-a-clinical-amyotrophic-lateral-sclerosis-cohort
#1
Fleur C Garton, Beben Benyamin, Qiongyi Zhao, Zhijun Liu, Jacob Gratten, Anjali K Henders, Zong-Hong Zhang, Janette Edson, Sarah Furlong, Sarah Morgan, Susan Heggie, Kathryn Thorpe, Casey Pfluger, Karen A Mather, Perminder S Sachdev, Allan F McRae, Matthew R Robinson, Sonia Shah, Peter M Visscher, Marie Mangelsdorf, Robert D Henderson, Naomi R Wray, Pamela A McCombe
BACKGROUND: Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants. METHODS: We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations...
July 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/28714954/c9orf72-expansion-disrupts-atm-mediated-chromosomal-break-repair
#2
Callum Walker, Saul Herranz-Martin, Evangelia Karyka, Chunyan Liao, Katherine Lewis, Waheba Elsayed, Vera Lukashchuk, Shih-Chieh Chiang, Swagat Ray, Padraig J Mulcahy, Mateusz Jurga, Ioannis Tsagakis, Tommaso Iannitti, Jayanth Chandran, Ian Coldicott, Kurt J De Vos, Mohamed K Hassan, Adrian Higginbottom, Pamela J Shaw, Guillaume M Hautbergue, Mimoun Azzouz, Sherif F El-Khamisy
Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA-RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks...
July 17, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28689190/intermediate-c9orf72-alleles-in-neurological-disorders-does-size-really-matter
#3
REVIEW
Adeline S L Ng, Eng-King Tan
C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of <20 hexanucleotide repeats are observed in controls, while up to thousands associate with disease. Intermediate C9orf72 repeat lengths, however, remain uncertain. We systematically reviewed the role of intermediate C9orf72 alleles in C9orf72-related neurological disorders. We identified 49 studies with adequate available data on normal or intermediate C9orf72 repeat length, involving subjects with FTD, ALS, Parkinson's disease (PD), atypical parkinsonism, Alzheimer's disease (AD) and other aetiologies...
July 8, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28677678/srsf1-dependent-nuclear-export-inhibition-of-c9orf72-repeat-transcripts-prevents-neurodegeneration-and-associated-motor-deficits
#4
Guillaume M Hautbergue, Lydia M Castelli, Laura Ferraiuolo, Alvaro Sanchez-Martinez, Johnathan Cooper-Knock, Adrian Higginbottom, Ya-Hui Lin, Claudia S Bauer, Jennifer E Dodd, Monika A Myszczynska, Sarah M Alam, Pierre Garneret, Jayanth S Chandran, Evangelia Karyka, Matthew J Stopford, Emma F Smith, Janine Kirby, Kathrin Meyer, Brian K Kaspar, Adrian M Isaacs, Sherif F El-Khamisy, Kurt J De Vos, Ke Ning, Mimoun Azzouz, Alexander J Whitworth, Pamela J Shaw
Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays...
July 5, 2017: Nature Communications
https://www.readbyqxmd.com/read/28666709/structural-and-functional-brain-signatures-of-c9orf72-in-motor-neuron-disease
#5
Federica Agosta, Pilar M Ferraro, Nilo Riva, Edoardo Gioele Spinelli, Teuta Domi, Paola Carrera, Massimiliano Copetti, Yuri Falzone, Maurizio Ferrari, Christian Lunetta, Giancarlo Comi, Andrea Falini, Angelo Quattrini, Massimo Filippi
This study investigated structural and functional magnetic resonance imaging abnormalities in hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) motor neuron disease (MND) relative to disease severity-matched sporadic MND cases. We enrolled 19 C9orf72 and 67 disease severity-matched sporadic MND patients, and 22 controls. Sporadic cases were grouped in patients with: no cognitive/behavioral deficits (sporadic-motor); same patterns of cognitive/behavioral impairment as C9orf72 cases (sporadic-cognitive); shorter disease duration versus other sporadic groups (sporadic-early)...
June 6, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28666471/heterogeneous-ribonuclear-protein-e2-hnrnp-e2-is-associated-with-tdp-43-immunoreactive-neurites-in-semantic-dementia-but-not-with-other-tdp-43-pathological-subtypes-of-frontotemporal-lobar-degeneration
#6
Yvonne S Davidson, Andrew C Robinson, Louis Flood, Sara Rollinson, Bridget C Benson, Yasmine T Asi, Anna Richardson, Matthew Jones, Julie S Snowden, Stuart Pickering-Brown, Tammaryn Lashley, David M A Mann
Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter personality and cognition. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP E2 was performed on sections of frontal and temporal cortex with hippocampus from 80 patients with FTLD, stratified by pathology 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 with no known mutation, and on 10 healthy controls...
June 30, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28660252/abnormal-expression-of-homeobox-genes-and-transthyretin-in-c9orf72-expansion-carriers
#7
NiCole A Finch, Xue Wang, Matthew C Baker, Michael G Heckman, Tania F Gendron, Kevin F Bieniek, Joanne Wuu, Mariely DeJesus-Hernandez, Patricia H Brown, Jeannie Chew, Karen R Jansen-West, Lillian M Daughrity, Alexandra M Nicholson, Melissa E Murray, Keith A Josephs, Joseph E Parisi, David S Knopman, Ronald C Petersen, Leonard Petrucelli, Bradley F Boeve, Neill R Graff-Radford, Yan W Asmann, Dennis W Dickson, Michael Benatar, Robert Bowser, Kevin B Boylan, Rosa Rademakers, Marka van Blitterswijk
OBJECTIVE: We performed a genome-wide brain expression study to reveal the underpinnings of diseases linked to a repeat expansion in chromosome 9 open reading frame 72 (C9ORF72). METHODS: The genome-wide expression profile was investigated in brain tissue obtained from C9ORF72 expansion carriers (n = 32), patients without this expansion (n = 30), and controls (n = 20). Using quantitative real-time PCR, findings were confirmed in our entire pathologic cohort of expansion carriers (n = 56) as well as nonexpansion carriers (n = 31) and controls (n = 20)...
August 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28642336/the-evolving-genetic-risk-for-sporadic-als
#8
Summer B Gibson, Jonathan M Downie, Spyridoula Tsetsou, Julie E Feusier, Karla P Figueroa, Mark B Bromberg, Lynn B Jorde, Stefan M Pulst
OBJECTIVE: To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity. METHODS: Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM...
June 22, 2017: Neurology
https://www.readbyqxmd.com/read/28639078/a-genome-wide-expression-association-analysis-identifies-genes-and-pathways-associated-with-amyotrophic-lateral-sclerosis
#9
Yanan Du, Yan Wen, Xiong Guo, Jingcan Hao, Wenyu Wang, Awen He, Qianrui Fan, Ping Li, Li Liu, Xiao Liang, Feng Zhang
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with strong genetic components. To identity novel risk variants for ALS, utilizing the latest genome-wide association studies (GWAS) and eQTL study data, we conducted a genome-wide expression association analysis by summary data-based Mendelian randomization (SMR) method. Summary data were derived from a large-scale GWAS of ALS, involving 12577 cases and 23475 controls. The eQTL annotation dataset included 923,021 cis-eQTL for 14,329 genes and 4732 trans-eQTL for 2612 genes...
June 21, 2017: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/28637276/repetitive-element-transcripts-are-elevated-in-the-brain-of-c9orf72-als-ftld-patients
#10
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
#11
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
#12
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
#13
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...
July 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28615433/disease-progression-in-c9orf72-mutation-carriers
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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