C9orf72

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C9orf72 repeat expansions are a rare genetic cause of parkinsonism.: C9ORF72 repeat expansion in parkinsonism

C9orf72 repeat expansions are a rare genetic cause of parkinsonism.: C9ORF72 repeat expansion in parkinsonism

(n>600). Although, the repeat size in our patients was clearly larger than in ethnically matched control subjects and their ages at onset were in the range observed in typical patients with C9ORF72 repeat expansions, we cannot completely exclude that the observed repeat expansions and the presence of typical PD are unrelated (i.e. the patients have two different neurological diseases). A recent study in a large cohort of 781 Caucasian PD cases, one third of which reported family histories of PD, failed to identify any pathogenic hexanucleotide expansions in C9ORF72, although a patient with typical PD harbored a marginally 38- GGGGCC hexanucleotide repeat allele (Majounie et al., 2012b). Large multi-centre studies worldwide are needed to determine the frequency of C9ORF72 mutations in idiopathic PD, particularly when positive family histories of parkinsonism, degenerative dementias or ALS are present.
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Gene co-expression analysis unravels a link between C9orf72 and RNA metabolism in myeloid cells

Gene co-expression analysis unravels a link between C9orf72 and RNA metabolism in myeloid cells

0.0002 PYCRL;CAD;PYCR2;CTPS1;PFAS;GLS A gene enrichment analysis was performed on the list of top 100 genes that are the most inversely correlated with C9orf72 mRNA levels. Left column: GO terms for which enrichment was found; middle column: p-values adjusted from Fisher exact test; right column: C9orf72 inversely correlated genes annotated with the corresponding GO term. AARS: alanyl-tRNA synthetase; CAD: carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase; CPTS1: CTP synthase 1; EARS2: glutamyl-tRNA synthetase 2, mitochondrial; EPRS: glutamyl-prolyl-tRNA synthetase; FARSA: phenylalanyl-tRNA synthetase, alpha subunit; GART: phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase; GEMIN5: gem (nuclear organelle) associated protein 5; GLS: glutaminase; IARS: isoleucyl-tRNA synthetase; PA2G4: proliferation-associated 2G4, 38kDa; PARS2: prolyl-tRNA synthetase 2, mitochondrial (putative); PDCD11: programmed cell death 11; PFAS: phosphoribosylformylglycinamidine synthase; POP1: processing of precursor 1, ribonuclease P/MRP subunit (S. cerevisiae); PYCR2: pyrroline-5-carboxylate reductase family, member 2; PYCRL: pyrroline-5-carboxylate reductase-like; TARS2; threonyl-tRNA synthetase 2, mitochondrial (putative); TRUB2: TruB pseudouridine (psi) synthase family member 2; UTP20: UTP20, small subunit (SSU) processome component, homolog (yeast)
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Dipeptide Repeat derived from C9orf72 Hexanucleotide Expansions Forms Amyloids or natively unfolded structures in vitro

Dipeptide Repeat derived from C9orf72 Hexanucleotide Expansions Forms Amyloids or natively unfolded structures in vitro

24. Flores BN, Dulchavsky ME, Krans A, Sawaya MR, Paulson HL, Todd PK, et al. Distinct c9orf72-associated dipeptide repeat structures correlate with neuronal toxicity. PLoS One. 2016. doi:10.1371/journal.pone.0165084 25. Chang YJ, Jeng US, Chiang YL, Hwang IS, Chen YR. The glycine-alanine dipeptide repeat from C9 or f72 hexanucleotide expansions forms toxic amyloids possessing cell- to-cell transmission properties. J Biol Chem. 2016. doi:10.1074/jbc.M115.694273

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Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

genetic- sporadic ALS patients. 48 Notably, there was no miRNA dysregulation in common between the aforementioned studies, nor between any of those studies on the brain and ours on plasma. Those discrepancies may stem from the heterogeneity of the previous autoptic cohorts and the differences in the methods of miRNA expression analysis. Noteworthy, and differently from our investigation, none of the patient cohorts mentioned in online supplemental table A5 were exclusively made up of C9orf72 carriers. Additionally, the observed differences between brain tissue and plasma miRNA profiles may be due to the tissue- specific expression of miRNA on the one hand, and to the time- dependent variations of detectable miRNAs all along the disease course on the other. Due to the disease process itself and other potential confounding factors, significant changes in miRNA expression are likely to occur between a relatively early phase of the disease, in which plasma miRNAs may be used as biomarkers, and the ultimate disease stage, at the moment of brain sampling. At this point, further miRNA profiling studies on C9orf72 brain tissue are needed to better understand whether tissue miRNAs correlate with plasma expression profiles and their contribution to the disease pathogenesis.
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Presymptomatic spinal cord pathology in c9orf72 mutation carriers: a longitudinal neuroimaging study

Presymptomatic spinal cord pathology in c9orf72 mutation carriers: a longitudinal neuroimaging study

The objective of this study was to characterise cervical spinal cord (SC) changes in asymptomatic c9orf72 hexanucleotide carriers. Methods: Seventy-two asymptomatic individuals were enrolled in a prospective study of first- degree relatives of ALS and FTD patients carrying the c9orf72 hexanucleotide expansion. Forty of them carried the pathogenic mutation (C9+). Each subject underwent quantitative cervical cord imaging. Structural grey (GM) and white matter (WM) metrics and diffusivity parameters were evaluated at baseline and 18 months later. Data were analysed in C9+ and C9- subgroups and C9+ subjects were further stratified by age.
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Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes

Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes

7 Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ. A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD. Neuron 2011;72(2):257-68.
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Étude de la toxicité causée par le gène C9orf72 dans la Sclérose Latérale Amyotrophique

Étude de la toxicité causée par le gène C9orf72 dans la Sclérose Latérale Amyotrophique

supported by the recent reports of two independent groups that have also developed C9orf72 mouse models but failed to observe neurodegeneration 246,247 . Both groups used a bacterial artificial chromosome (BAC) system to express a partial (exons 1-6) or full length human C9orf72 that comprised a pathogenic GGGGCC repeat (ranging from 100- 1,000 units long). Overall, mouse model data have revealed that even if RNA foci and different dipeptides were produced in glial cells and neurons, neurodegeneration and motility impairments were not observed, even at advanced age, in the animals 246,247 . Also, it appears that animals did not openly exhibit cognitive features similar to other FTD mouse models 246,247 . Taken together, these results suggest that neither cognitive deficit nor motor deficit could be caused only by the expression of human C9orf72 harbouring a pathogenic repeat in mice.
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en fr Modeling C9ORF72 loss-of-function : a knockdown mouse model Caractérisation de la perte de fonction de C9ORF72 : un nouveau modèle knockdown

26 1.3. p62, a link between autophagy and the ubiquitin proteasome system Autophagy is a key aspect of cellular homeostasis, and as previously seen, its failure causes various effects associated with neurodegeneration such as alterations in local axonal membrane trafficking and turnover (Komatsu et al., 2007). Its coordinated role with other protein degradation pathways allows for clearance of aggregating proteins that accumulate during disease. Several proteins link degradation pathway in a coordinated manner, of which, p62 has a particular role. p62, also known as sequestosome 1 (SQSTM1), is a multi-complex ubiquitin binding protein that recognizes toxic cellular waste and facilitates degradation through the UPS or through autophagosome-lysosome pathways (Bitto et al., 2014; Lin et al., 2013). The p62 protein is commonly found in inclusion bodies containing polyubiquitinated protein aggregates and expressed in stressful conditions such as oxygen radical stress and inhibition of proteasomal activity. It is also found in the brain of C9orf72 mutation carriers, under the form of TDP43 negative, ubiquitin positive inclusions. Of notice, mutations in the p62 gene can cause classical, adult onset Paget bone disease and FTD/ALS (Rea et al., 2014). It is a multifunctional protein capable of binding to ubiquitin at the surface of protein aggregates through an ubiquitin-associated (UBA) domain. Through this interaction, p62 brings autophagosome formation by linking with a LC3-interacting region (LIR) in a highly selective manner to ensure protein degradation (Birgisdottir et al., 2013; Pankiv et al., 2007);. The primary sequence of p62 has two nuclear localization signals (NLS) and one nuclear export signal (NES), allowing the protein to shuttle between nucleus and cytoplasm (Bitto et al., 2014). Another function of p62 has been described in amino acid sensing by its association with the mTORC1 complex subunit “Raptor”, and with several other Rab GTPases. The Rab protein family is implicated in regulation of multiple steps of membrane trafficking, including vesicle formation, vesicle movement along tubulin and actin networks, and membrane fusion. Through this interaction, p62 relays information from amino acid pool to the mTOR pathway, probably acting as a control mechanism to prevent excess autophagy and to avoid amino acid starvation (Bitto et al., 2014). Almost all inclusions of protein aggregates are p62 positive in autophagy deficient cells, suggesting that protein complexes aggregate in a p62 dependent manner (Komatsu et al., 2007). Furthermore, in several neurodegenerative diseases, protein aggregates co-localize with p62 (Bitto et al., 2014; Rea et al., 2014).
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Génération de lignées de poissons-zèbres par génie génétique dans le cadre de l'étude du gène C9orf72

Génération de lignées de poissons-zèbres par génie génétique dans le cadre de l'étude du gène C9orf72

faible efficacité pour la technique d’insertion de séquences précises à un site spécifique utilisant le système CRISPR/Cas9. En effet, pour l’utilisation du système CRIPSR/Cas9, l’efficacité maximale des RDH guidées avec une matrice d’ADN ODNsb a été démontrée dans une étude récente sur le poisson-zèbre comme oscillant entre 4-8% lorsque optimisée [247]. De plus, si l’on ne considère que les réparations dites parfaites permettant l’insertion au site exact désiré sans l’intégration d’indels indésirables, ce qui est nécessaire pour l’insertion de tags qui doivent être dans le cadre de lecture du gène ciblé afin d’être exprimés et détectés par nos techniques de criblage, alors les taux maximaux d’efficacité d’insertion observés sont réduits à des valeurs encore plus basses de seulement 1-4% [247]. Notons que ces taux sont rapportés pour des KI de séquences ne différant des séquences originales des gènes ciblés que par des substitutions non contiguës de 5 nucléotides, dont l’intégration est vraisemblablement plus efficace que pour nos insertions de 36 pb (12xHis) et 717 pb (eGFP) de taille considérablement plus élevée, dont la séquence hors des bras d’homologie de leur matrice ne présentent pas d’homologie avec la séquence cible [233, 234]. Qui plus est, une étude chez le poisson-zèbre pour laquelle a été effectué l’insertion d’une séquence résultant en la substitution de 5 nucléotides non contiguës, à l’aide du même système CRISPR/Cas9 que nous avons employé et de matrices d’ADN ODNsb, a rapporté que le taux d’efficacité le plus élevé obtenu d’intégration dans la lignée germinale, permettant la transmission du KI à une génération subséquente, a été de 4% [248,249]. Enfin, même lorsqu’il y a intégration dans la lignée germinale, le taux de transmission des intégrations sans erreur peut s’avérer aussi relativement bas avec des valeurs rapportées récemment allant de moins de 0.1 % à 23%. [247]. Ainsi, bien qu’un nombre de poissons F0 injectés prévu d’être statistiquement adéquat pour avoir une probabilité raisonnable d’obtenir au moins un spécimen en mesure de transmettre l’intégration du tag désiré sans erreur a été criblés pour nos lignées C9orf72 NHis et C9orf72 CGFP , notre échec à identifier un poisson
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White matter lesions in FTLD: distinct phenotypes characterize GRN and C9ORF72 mutations

White matter lesions in FTLD: distinct phenotypes characterize GRN and C9ORF72 mutations

Methods. Patients. We retrospectively collected clin- ical and MRI data from 28 patients with a diagnosis of bv-FTLD based on the Rascovsky criteria, 4 includ- ing 11 GRN mutation carriers and 17 C9ORF72 mutation carriers. One patient with multiple cardio- vascular risk factors was excluded from this study; all other patients had no cardiovascular risk factors apart from sex, age, or treated and well-controlled hyper- tension. Age at onset was determined as the time of symptom appearance reported by the closest relative of the patient. A group of 11 age-matched healthy individuals were used as controls. Two GRN patients have been reported in a previous publication. 1 This retrospective study was approved by our institutional review board. Informed consent was obtained accord- ing to the French legislation for clinical genetic studies.
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