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https://www.readbyqxmd.com/read/29325606/repeat-expansion-diseases
#1
Henry Paulson
More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease, and eight other polyglutamine disorders, including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (fragile X syndrome)...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29323119/cug-initiation-and-frameshifting-enable-production-of-dipeptide-repeat-proteins-from-als-ftd-c9orf72-transcripts
#2
Ricardos Tabet, Laure Schaeffer, Fernande Freyermuth, Melanie Jambeau, Michael Workman, Chao-Zong Lee, Chun-Chia Lin, Jie Jiang, Karen Jansen-West, Hussein Abou-Hamdan, Laurent Désaubry, Tania Gendron, Leonard Petrucelli, Franck Martin, Clotilde Lagier-Tourenne
Expansion of G4C2 repeats in the C9ORF72 gene is the most prevalent inherited form of amyotrophic lateral sclerosis and frontotemporal dementia. Expanded transcripts undergo repeat-associated non-AUG (RAN) translation producing dipeptide repeat proteins from all reading frames. We determined cis-factors and trans-factors influencing translation of the human C9ORF72 transcripts. G4C2 translation operates through a 5'-3' cap-dependent scanning mechanism, requiring a CUG codon located upstream of the repeats and an initiator Met-tRNAMeti...
January 11, 2018: Nature Communications
https://www.readbyqxmd.com/read/29316893/frequency-of-sca8-sca10-sca12-sca36-fxtas-and-c9orf72-repeat-expansions-in-sca-patients-negative-for-the-most-common-sca-subtypes
#3
Gülsah Aydin, Gabriele Dekomien, Sabine Hoffjan, Wanda Maria Gerding, Jörg T Epplen, Larissa Arning
BACKGROUND: Spinocerebellar ataxia (SCA) subtypes are often caused by expansions in non-coding regions of genes like SCA8, SCA10, SCA12 and SCA36. Other ataxias are known to be associated with repeat expansions such as fragile X-associated tremor ataxia syndrome (FXTAS) or expansions in the C9orf72 gene. When no mutation has been identified in the aforementioned genes next-generation sequencing (NGS)-based diagnostics may also be applied. In order to define an optimal diagnostic strategy, more information about the frequency and phenotypic characteristics of rare repeat expansion disorders associated with ataxia should be at hand...
January 9, 2018: BMC Neurology
https://www.readbyqxmd.com/read/29313812/pathogenic-commonalities-between-spinal-muscular-atrophy-and-amyotrophic-lateral-sclerosis-converging-roads-to-therapeutic-development
#4
REVIEW
Melissa Bowerman, Lyndsay M Murrray, Frédérique Scamps, Bernard L Schneider, Rashmi Kothary, Cédric Raoul
Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the two most common motoneuron disorders, which share typical pathological hallmarks while remaining genetically distinct. Indeed, SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene whilst ALS, albeit being mostly sporadic, can also be caused by mutations within genes, including superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS), TAR DNA-binding protein 43 (TDP-43) and chromosome 9 open reading frame 72 (C9ORF72)...
December 4, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29311743/tdp-43-pathology-disrupts-nuclear-pore-complexes-and-nucleocytoplasmic-transport-in-als-ftd
#5
Ching-Chieh Chou, Yi Zhang, Mfon E Umoh, Spencer W Vaughan, Ileana Lorenzini, Feilin Liu, Melissa Sayegh, Paul G Donlin-Asp, Yu Han Chen, Duc M Duong, Nicholas T Seyfried, Maureen A Powers, Thomas Kukar, Chadwick M Hales, Marla Gearing, Nigel J Cairns, Kevin B Boylan, Dennis W Dickson, Rosa Rademakers, Yong-Jie Zhang, Leonard Petrucelli, Rita Sattler, Daniela C Zarnescu, Jonathan D Glass, Wilfried Rossoll
The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery...
January 8, 2018: Nature Neuroscience
https://www.readbyqxmd.com/read/29302778/a-zebrafish-model-for-c9orf72-als-reveals-rna-toxicity-as-a-pathogenic-mechanism
#6
Bart Swinnen, Andre Bento-Abreu, Tania F Gendron, Steven Boeynaems, Elke Bogaert, Rik Nuyts, Mieke Timmers, Wendy Scheveneels, Nicole Hersmus, Jiou Wang, Sarah Mizielinska, Adrian M Isaacs, Leonard Petrucelli, Robin Lemmens, Philip Van Damme, Ludo Van Den Bosch, Wim Robberecht
The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci...
January 4, 2018: Acta Neuropathologica
https://www.readbyqxmd.com/read/29302060/c9orf72-ggggcc-repeat-associated-non-aug-translation-is-upregulated-by-stress-through-eif2%C3%AE-phosphorylation
#7
Weiwei Cheng, Shaopeng Wang, Alexander A Mestre, Chenglai Fu, Andres Makarem, Fengfan Xian, Lindsey R Hayes, Rodrigo Lopez-Gonzalez, Kevin Drenner, Jie Jiang, Don W Cleveland, Shuying Sun
Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC) n -containing RNAs into poly-dipeptides can initiate in vivo without a 5'-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2α), the core event of an integrated stress response (ISR)...
January 4, 2018: Nature Communications
https://www.readbyqxmd.com/read/29282338/unaffected-mosaic-c9orf72-case-rna-foci-dipeptide-proteins-but-upregulated-c9orf72-expression
#8
Philip McGoldrick, Ming Zhang, Marka van Blitterswijk, Christine Sato, Danielle Moreno, Shangxi Xiao, Ashley B Zhang, Paul M McKeever, Anna Weichert, Raphael Schneider, Julia Keith, Leonard Petrucelli, Rosa Rademakers, Lorne Zinman, Janice Robertson, Ekaterina Rogaeva
OBJECTIVE: Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include C9orf72 haploinsufficiency, G4C2/C4G2 RNA foci, and dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, the role of small expansions (e.g., 30-90 repeats) is unknown and was investigated here. METHODS: We conducted a molecular and pathology study of a family in which the father (unaffected at age 90) carried a 70-repeat allele in blood DNA that expanded to ≈1,750 repeats in his children, causing ALS...
December 27, 2017: Neurology
https://www.readbyqxmd.com/read/29281254/structural-and-dynamical-characterization-of-dna-and-rna-quadruplexes-obtained-from-the-ggggcc-and-gggcct-hexanucleotide-repeats-associated-with-c9ftd-als-and-sca36-diseases
#9
Yuan Zhang, Christopher Roland, Celeste Sagui
A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene has been considered the major cause behind both frontotemporal dementia and amyotrophic lateral sclerosis, while a (GGGCCT) is associated with spinocerebellar ataxia 36. Recent experiments involving NMR, CD, optical melting and 1D ^1H NMR spectroscopy, suggest that the r(GGGGCC) HR can adopt a hairpin structure with G-G mismatches in equilibrium with a G-quadruplex structure. G-quadruplexes have also been identified for d(GGGGCC). As these experiments lack molecular resolution, we have used molecular dynamics microsecond simulations to obtain a structural characterization of the G-quadruplexes associated with both HRs...
December 27, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29274668/atxn1-intermediate-length-polyglutamine-expansions-are-associated-with-amyotrophic-lateral-sclerosis
#10
Serena Lattante, Maria Grazia Pomponi, Amelia Conte, Giuseppe Marangi, Giulia Bisogni, Agata Katia Patanella, Emiliana Meleo, Christian Lunetta, Nilo Riva, Lorena Mosca, Paola Carrera, Marco Bee, Marcella Zollino, Mario Sabatelli
To clarify the possible involvement of intermediate ATXN1 alleles as risk factors for amyotrophic lateral sclerosis (ALS), we tested ATXN1 in a cohort of 1146 Italian ALS patients, previously screened for variants in other ALS genes, and in 529 controls. We detected ATXN1 alleles with ≥33 polyglutamine repeats in 105 of 1146 patients (9.16%) and 29 of 529 controls (5.48%) (p = 0.003). The frequency of ATXN1 alleles with ≥33 polyglutamine repeats was particularly high in the group of ALS patients carrying the C9orf72 expansion (12/59, 20...
November 28, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29274339/thermodynamic-and-spectroscopic-investigations-of-tmpyp4-association-with-guanine-and-cytosine-rich-dna-and-rna-repeats-of-c9orf72
#11
Hasan Alniss, Bita Zamiri, Melisa Khalaj, Christopher E Pearson, Robert B Macgregor
BACKGROUND: An expansion of the hexanucleotide repeat (GGGGCC)n·(GGCCCC)n in the C9orf72 promoter has been shown to be the cause of Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). The C9orf72 repeat can form four-stranded structures; the cationic porphyrin (TMPyP4) binds and distorts these structures. METHODS: Isothermal titration calorimetry (ITC), and circular dichroism (CD) were used to study the binding of TMPyP4 to the C-rich and G-rich DNA and RNA oligos containing the hexanucleotide repeat at pH 7...
December 20, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29262335/als-ftd-associated-c9orf72-repeat-rna-promotes-phase-transitions-in%C3%A2-vitro-and-in-cells
#12
Marta M Fay, Paul J Anderson, Pavel Ivanov
Membraneless RNA granules originate via phase separation events driven by multivalent interactions. As RNA is the defining component of such granules, we examined how RNA contributes to granule assembly. Expansion of hexanucleotide GGGGCC (G4C2) repeats in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). We describe a biophysical phenomenon whereby G4C2 RNA (rG4C2) promotes the phase separation of RNA granule proteins in vitro and in cells...
December 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/29226869/the-heritability-of-frontotemporal-lobar-degeneration-validation-of-pedigree-classification-criteria-in-a-northern-italy-cohort
#13
Silvia Fostinelli, Miriam Ciani, Roberta Zanardini, Orazio Zanetti, Giuliano Binetti, Roberta Ghidoni, Luisa Benussi
A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria...
December 8, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29222490/ran-translation-at-c9orf72-associated-repeat-expansions-is-selectively-enhanced-by-the-integrated-stress-response
#14
Katelyn M Green, M Rebecca Glineburg, Michael G Kearse, Brittany N Flores, Alexander E Linsalata, Stephen J Fedak, Aaron C Goldstrohm, Sami J Barmada, Peter K Todd
Repeat-associated non-AUG (RAN) translation allows for unconventional initiation at disease-causing repeat expansions. As RAN translation contributes to pathogenesis in multiple neurodegenerative disorders, determining its mechanistic underpinnings may inform therapeutic development. Here we analyze RAN translation at G4C2 repeat expansions that cause C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9RAN) and at CGG repeats that cause fragile X-associated tremor/ataxia syndrome...
December 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/29216908/clinical-and-neuropathological-features-of-als-ftd-with-tia1-mutations
#15
Veronica Hirsch-Reinshagen, Cyril Pottier, Alexandra M Nicholson, Matt Baker, Ging-Yuek R Hsiung, Charles Krieger, Pheth Sengdy, Kevin B Boylan, Dennis W Dickson, Marsel Mesulam, Sandra Weintraub, Eileen Bigio, Lorne Zinman, Julia Keith, Ekaterina Rogaeva, Sasha A Zivkovic, David Lacomis, J Paul Taylor, Rosa Rademakers, Ian R A Mackenzie
Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years)...
December 7, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29197216/early-cognitive-structural-and-microstructural-changes-in-presymptomatic-c9orf72-carriers-younger-than-40-years
#16
Anne Bertrand, Junhao Wen, Daisy Rinaldi, Marion Houot, Sabrina Sayah, Agnès Camuzat, Clémence Fournier, Sabrina Fontanella, Alexandre Routier, Philippe Couratier, Florence Pasquier, Marie-Odile Habert, Didier Hannequin, Olivier Martinaud, Paola Caroppo, Richard Levy, Bruno Dubois, Alexis Brice, Stanley Durrleman, Olivier Colliot, Isabelle Le Ber
Importance: Presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation, the most frequent genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. Objectives: To assess the occurrence of cognitive, structural, and microstructural changes in presymptomatic C9orf72 carriers...
December 2, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/29196813/sense-encoded-poly-gr-dipeptide-repeat-proteins-correlate-to-neurodegeneration-and-uniquely-co-localize-with-tdp-43-in-dendrites-of-repeat-expanded-c9orf72-amyotrophic-lateral-sclerosis
#17
Shahram Saberi, Jennifer E Stauffer, Jie Jiang, Sandra Diaz Garcia, Amy E Taylor, Derek Schulte, Takuya Ohkubo, Cheyenne L Schloffman, Marcus Maldonado, Michael Baughn, Maria J Rodriguez, Don Pizzo, Don Cleveland, John Ravits
Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models...
December 1, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/29193335/c9orf72-repeat-expansions-as-genetic-modifiers-for-depression-in-spinocerebellar-ataxias
#18
Karla P Figueroa, Shi-Rui Gan, Susan Perlman, George Wilmot, Christopher M Gomez, Jeremy Schmahmann, Henry Paulson, Vikram G Shakkottai, Sarah H Ying, Theresa Zesiewicz, Khalaf Bushara, Michael Geschwind, Guangbin Xia, S H Subramony, Tetsuo Ashizawa, Stefan M Pulst, Sheng-Han Kuo
No abstract text is available yet for this article.
November 29, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29191947/a-proteomic-network-approach-across-the-als-ftd-disease-spectrum-resolves-clinical-phenotypes-and-genetic-vulnerability-in-human-brain
#19
Mfon E Umoh, Eric B Dammer, Jingting Dai, Duc M Duong, James J Lah, Allan I Levey, Marla Gearing, Jonathan D Glass, Nicholas T Seyfried
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlap in clinical presentation, neuropathology, and genetic underpinnings. The molecular basis for the overlap of these disorders is not well established. We performed a comparative unbiased mass spectrometry-based proteomic analysis of frontal cortical tissues from postmortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the C9orf72 expansion mutation, the most common genetic cause of both ALS and FTD Our systems-level analysis of the brain proteome integrated both differential expression and co-expression approaches to assess the relationship of these differences to clinical and pathological phenotypes...
November 30, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29182198/-abnormal-expansion-of-c9orf72-gene-in-familial-frontotemporal-dementia
#20
Marcelo Miranda C, M Leonor Bustamante C, Luisa Herrera C
Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND) may share similar pathogenic mechanisms. An abnormal hexanucleotide expansion in C9orf72 gene is the most common genetic abnormality of these conditions and explains their concurrence in the same family. We report a 77-year-old female presenting with non-fluent aphasia leading to mutism and a mild Parkinsonism. A magnetic resonance imaging showed a severe atrophy of frontal and temporal lobes. Several family members of the patient suffered of atypical Parkinsonism, lateral amyotrophic sclerosis and dementia...
July 2017: Revista Médica de Chile
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