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C9orf72

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https://www.readbyqxmd.com/read/28325066/comprehensive-analysis-to-explain-reduced-or-increased-sod1-enzymatic-activity-in-als-patients-and-their-relatives
#1
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
#2
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
https://www.readbyqxmd.com/read/28319737/relationship-between-c9orf72-repeat-size-and-clinical-phenotype
#3
REVIEW
Sara Van Mossevelde, Julie van der Zee, Marc Cruts, Christine Van Broeckhoven
Patient carriers of a C9orf72 repeat expansion exhibit remarkable heterogeneous clinical and pathological characteristics suggesting the presence of modifying factors. In accordance with other repeat expansion diseases, repeat length is the prime candidate as a genetic modifier. Observations of earlier onset ages in younger generations of large families suggested a mechanism of disease anticipation. Yet, studies of repeat size and onset age have led to conflicting results. Also, the correlation between repeat size and diagnosis is poorly understood...
March 17, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28319438/systemic-deregulation-of-autophagy-upon-loss-of-als-and-ftd-linked-c9orf72
#4
Yon Ji, Janet Ugolino, Nathan Ryan Brady, Anne Hamacher-Brady, Jiou Wang
A genetic mutation in the C9orf72 gene causes the most common forms of neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 protein, predicted to be a DENN-family protein, is reduced in ALS and FTD, but its functions remain poorly understood. Using a 3110043O21Rik/C9orf72 knockout mouse model, as well as cellular analysis, we have found that loss of C9orf72 causes alterations in the signaling states of central autophagy regulators. In particular, C9orf72 depletion leads to reduced activity of MTOR, a negative regulator of macroautophagy/autophagy, and concomitantly increased TFEB levels and nuclear translocation...
March 20, 2017: Autophagy
https://www.readbyqxmd.com/read/28306503/phase-separation-of-c9orf72-dipeptide-repeats-perturbs-stress-granule-dynamics
#5
Steven Boeynaems, Elke Bogaert, Denes Kovacs, Albert Konijnenberg, Evy Timmerman, Alex Volkov, Mainak Guharoy, Mathias De Decker, Tom Jaspers, Veronica H Ryan, Abigail M Janke, Pieter Baatsen, Thomas Vercruysse, Regina-Maria Kolaitis, Dirk Daelemans, J Paul Taylor, Nancy Kedersha, Paul Anderson, Francis Impens, Frank Sobott, Joost Schymkowitz, Frederic Rousseau, Nicolas L Fawzi, Wim Robberecht, Philip Van Damme, Peter Tompa, Ludo Van Den Bosch
Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28268100/intrafamilial-variable-phenotype-including-corticobasal-syndrome-in-a-family-with-p-p301l-mutation-in-the-mapt-gene-first-report-in-south-america
#6
Emilia M Gatto, Ricardo F Allegri, Gustavo Da Prat, Patricio Chrem Mendez, David S Hanna, Michael O Dorschner, Ezequiel I Surace, Cyrus P Zabetian, Ignacio F Mata
Frontotemporal lobar degeneration is a neuropathological disorder that causes a variety of clinical syndromes including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal syndrome (CBS). FTD associated with parkinsonism occurs frequently as a result of mutations in the C9orf72 gene and also in the genes coding for the protein associated with microtubule tau (MAPT) and progranulin (GRN) on chromosome 17 (FTDP-17). Herein, we report an Argentinean family, of Basque ancestry, with an extensive family history of behavioral variant of FTD...
February 10, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28266105/c9orf72-at-the-intersection-of-lysosome-cell-biology-and-neurodegenerative-disease
#7
REVIEW
Joseph Amick, Shawn M Ferguson
The discovery that expansion of a hexanucleotide repeat within a non-coding region of the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia raised questions about C9orf72 protein function and potential disease relevance. The major predicted structural feature of the C9orf72 protein is a DENN domain. As DENN domains are best characterized for regulation of specific Rab GTPases, it has been proposed that C9orf72 may also act through regulation of a GTPase target. Recent genetic and cell biological studies furthermore indicate that the C9orf72 protein functions at lysosomes as part of a larger complex that also contains the Smith-Magenis Chromosome Region 8 (SMCR8) and WD repeat-containing protein 41 (WDR41) proteins...
March 7, 2017: Traffic
https://www.readbyqxmd.com/read/28264768/clinical-and-genetic-analyses-of-familial-and-sporadic-frontotemporal-dementia-patients-in-southern-italy
#8
Rosa Capozzo, Celeste Sassi, Monia B Hammer, Simona Arcuti, Chiara Zecca, Maria R Barulli, Rosanna Tortelli, J Raphael Gibbs, Cynthia Crews, Davide Seripa, Francesco Carnicella, Claudia Dell'Aquila, Marco Rossi, Filippo Tamma, Francesco Valluzzi, Bruno Brancasi, Francesco Panza, Andrew B Singleton, Giancarlo Logroscino
INTRODUCTION: We investigated the clinical differences between familial and sporadic frontotemporal dementia (FTD), screening for mutations in known FTD genes. METHODS: We diagnosed 22 affected individuals belonging to eight families and 43 sporadic cases with FTD in Apulia, Southern Italy, in 2 years. Mutations in common causative FTD genes (GRN, MAPT, VCP, and TARDBP) and C9ORF72 expansions were screened. RESULTS: Behavioral variant of FTD was the most common clinical subtype (50% and 69% in familial and sporadic cases, respectively)...
March 3, 2017: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/28251139/loss-of-c9orf72-function-leads-to-autoimmunity
#9
COMMENT
Lazaros I Sakkas, Dimitrios P Bogdanos, Eleni E Kousvelari
No abstract text is available yet for this article.
February 2017: Annals of Translational Medicine
https://www.readbyqxmd.com/read/28243191/the-role-of-dipeptide-repeats-in-c9orf72-related-als-ftd
#10
REVIEW
Brian D Freibaum, J Paul Taylor
Expansion of a hexanucleotide (GGGGCC) repeat in the gene chromosome 9 open reading frame 72 (C9ORF72) is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). Three non-exclusive mechanisms have been proposed to contribute to the pathology initiated by this genetic insult. First, it was suggested that decreased expression of the C9orf72 protein product may contribute to disease. Second, the recognition that C9ORF72-related disease is associated with accumulation of GGGGCC repeat-containing RNA in nuclear foci led to the suggestion that toxic gain of RNA function, perhaps related to sequestration of RNA-binding proteins, might be an important driver of disease...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28238272/psychiatric-presentations-of-c9orf72-mutation-what-are-the-diagnostic-implications-for-clinicians
#11
Simon Ducharme, Sepideh Bajestan, Bradford C Dickerson, Valerie Voon
The C9orf72 mutation was identified as the most frequent genetic cause of frontotemporal dementia (FTD). In light of multiple reports of predominant psychiatric presentations of FTD secondary to C9orf72 mutation, the American Neuropsychiatric Association Committee on Research reviewed all studies on psychiatric aspects of this mutation to identify clinically relevant features for diagnosis. The most common psychiatric presentation is psychosis (21%-56%), with delusions, and/or multimodal hallucinations. Other presentations include late-onset mania and depression with cognitive impairment or catatonia...
February 27, 2017: Journal of Neuropsychiatry and Clinical Neurosciences
https://www.readbyqxmd.com/read/28222900/genetic-analysis-of-the-sod1-and-c9orf72-genes-in-hungarian-patients-with-amyotrophic-lateral-sclerosis
#12
Kornélia Tripolszki, Bernadett Csányi, Dóra Nagy, Antonia Ratti, Cinzia Tiloca, Vincenzo Silani, Éva Kereszty, Nóra Török, László Vécsei, József I Engelhardt, Péter Klivényi, Nikoletta Nagy, Márta Széll
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of motor neurons. To date, more than 20 genes have been implicated in ALS, and of these, the 2 most frequently mutated are the superoxide dismutase 1 (SOD1) gene and the chromosome 9 open reading frame 72 (C9ORF72) gene. In this study, we aimed to investigate the contribution of these 2 Mendelian genes to the development of the disease in Hungarian ALS patients (n = 66). Direct sequencing of the SOD1 gene revealed a novel (p...
January 29, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28197542/the-proline-arginine-dipeptide-from-hexanucleotide-repeat-expanded-c9orf72-inhibits-the-proteasome
#13
Rahul Gupta, Matthews Lan, Jelena Mojsilovic-Petrovic, Won Hoon Choi, Nathaniel Safren, Sami Barmada, Min Jae Lee, Robert Kalb
An intronic hexanucleotide repeat expansion (HRE) mutation in the C9ORF72 gene is the most common cause of familial ALS and frontotemporal dementia (FTD) and is found in ∼7% of individuals with apparently sporadic disease. Several different diamino acid peptides can be generated from the HRE by noncanonical translation (repeat-associated non-ATG translation, or RAN translation), and some of these peptides can be toxic. Here, we studied the effects of two arginine containing RAN translation products [proline/arginine repeated 20 times (PR20) and glycine/arginine repeated 20 times (GR20)] in primary rat spinal cord neuron cultures grown on an astrocyte feeder layer...
January 2017: ENeuro
https://www.readbyqxmd.com/read/28195531/multiplex-image-based-autophagy-rnai-screening-identifies-smcr8-as-ulk1-kinase-activity-and-gene-expression-regulator
#14
Jennifer Jung, Arnab Nayak, Véronique Schaeffer, Tatjana Starzetz, Achim K Kirsch, Stefan Müller, Ivan Dikic, Michel Mittelbronn, Christian Behrends
Autophagy is an intracellular recycling and degradation pathway that depends on membrane trafficking. Rab GTPases are central for autophagy but their regulation especially through the activity of Rab GEFs remains largely elusive. We employed a RNAi screen simultaneously monitoring different populations of autophagosomes and identified 34 out of 186 Rab GTPase, GAP and GEF family members as potential autophagy regulators, amongst them SMCR8. SMCR8 uses overlapping binding regions to associate with C9ORF72 or with a C9ORF72-ULK1 kinase complex holo-assembly, which function in maturation and formation of autophagosomes, respectively...
February 14, 2017: ELife
https://www.readbyqxmd.com/read/28192553/clinical-evidence-of-disease-anticipation-in-families-segregating-a-c9orf72-repeat-expansion
#15
Sara Van Mossevelde, Julie van der Zee, Ilse Gijselinck, Kristel Sleegers, Jan De Bleecker, Anne Sieben, Rik Vandenberghe, Tim Van Langenhove, Jonathan Baets, Olivier Deryck, Patrick Santens, Adrian Ivanoiu, Christiana Willems, Veerle Bäumer, Marleen Van den Broeck, Karin Peeters, Maria Mattheijssens, Peter De Jonghe, Patrick Cras, Jean-Jacques Martin, Marc Cruts, Peter P De Deyn, Sebastiaan Engelborghs, Christine Van Broeckhoven
Importance: Patients carrying a C9orf72 repeat expansion leading to frontotemporal dementia and/or amyotrophic lateral sclerosis have highly variable ages at onset of disease, suggesting the presence of modifying factors. Objective: To provide clinical-based evidence for disease anticipation in families carrying a C9orf72 repeat expansion by analyzing age at onset, disease duration, and age at death in successive generations. Design, Setting, and Participants: This cohort study was performed from June 16, 2000, to June 1, 2016, in 36 extended Belgian families in which a C9orf72 repeat expansion was segregating...
February 13, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/28167899/cysteine-modifications-in-the-pathogenesis-of-als
#16
REVIEW
Cristiana Valle, Maria Teresa Carrì
Several proteins are found misfolded and aggregated in sporadic and genetic forms of amyotrophic lateral sclerosis (ALS). These include superoxide dismutase (SOD1), transactive response DNA-binding protein (TDP-43), fused in sarcoma/translocated in liposarcoma protein (FUS/TLS), p62, vasolin-containing protein (VCP), Ubiquilin-2 and dipeptide repeats produced by unconventional RAN-translation of the GGGGCC expansion in C9ORF72. Up to date, functional studies have not yet revealed a common mechanism for the formation of such diverse protein inclusions...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28160950/comprehensive-targeted-next-generation-sequencing-in-japanese-familial-amyotrophic-lateral-sclerosis
#17
Ayumi Nishiyama, Tetsuya Niihori, Hitoshi Warita, Rumiko Izumi, Tetsuya Akiyama, Masaaki Kato, Naoki Suzuki, Yoko Aoki, Masashi Aoki
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons. We have recently identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan. To reveal possible genetic causes for the remaining 51 patients with familial ALS (45 pedigrees), we performed targeted next-generation sequencing of 35 known ALS/motor neuron diseases-related genes. Known variants in ANG, OPTN, SETX, and TARDBP were identified in 6 patients...
January 10, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28159885/genetic-testing-in-als-a-survey-of-current-practices
#18
REVIEW
Alice Vajda, Russell L McLaughlin, Mark Heverin, Owen Thorpe, Sharon Abrahams, Ammar Al-Chalabi, Orla Hardiman
OBJECTIVE: To determine the degree of consensus among clinicians on the clinical use of genetic testing in amyotrophic lateral sclerosis (ALS) and the factors that determine decision-making. METHODS: ALS researchers worldwide were invited to participate in a detailed online survey to determine their attitudes and practices relating to genetic testing. RESULTS: Responses from 167 clinicians from 21 different countries were analyzed. The majority of respondents (73...
March 7, 2017: Neurology
https://www.readbyqxmd.com/read/28158451/c9orf72-hexanucleotide-repeat-exerts-toxicity-in-a-stable-inducible-motor-neuronal-cell-model-which-is-rescued-by-partial-depletion-of-pten
#19
Matthew J Stopford, Adrian Higginbottom, Guillaume M Hautbergue, Johnathan Cooper-Knock, Padraig J Mulcahy, Kurt J De Vos, Alan E Renton, Hannah Pliner, Andrea Calvo, Adriano Chio, Bryan J Traynor, Mimoun Azzouz, Paul R Heath, Italsgen Consortium, NeuroX Consortium, Janine Kirby, Pamela J Shaw
No abstract text is available yet for this article.
February 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28148298/tbk1-a-new-player-in-als-linking-autophagy-and-neuroinflammation
#20
REVIEW
James A Oakes, Maria C Davies, Mark O Collins
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder affecting motor neurons, resulting in progressive muscle weakness and death by respiratory failure. Protein and RNA aggregates are a hallmark of ALS pathology and are thought to contribute to ALS by impairing axonal transport. Mutations in several genes known to contribute to ALS result in deposition of their protein products as aggregates; these include TARDBP, C9ORF72, and SOD1. In motor neurons, this can disrupt transport of mitochondria to areas of metabolic need, resulting in damage to cells and can elicit a neuroinflammatory response leading to further neuronal damage...
February 2, 2017: Molecular Brain
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