Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Expression of human C9ORF72 hexanucleotide expansion reproduces RNA foci and dipeptide repeat proteins but not neurodegeneration in BAC transgenic mice

ABSTRACT: Nuclear RNA foci are often associated with mis-regulation of RNA processing in repeat expansion diseases. Here we report transcriptomic analysis of mice expressing expanded G4C2 repeats, the most common genetic cause of FTD/ALS. We show that the presence of numerous nuclear G4C2 repeat RNA foci does not cause extensive changes in RNA processing in this model organism.

ORGANISM(S): Mus musculus

PROVIDER: GSE74973 | GEO | 2015/11/14

SECONDARY ACCESSION(S): PRJNA302110

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Differential Toxicity of Nuclear RNA Foci Versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS

Project description:Nuclear RNA foci are often associated with mis-regulation of RNA processing in repeat expansion diseases. Here we report transcriptomic analysis of flies carrying expanded G4C2 repeats, the most common genetic cause of FTD/ALS. By obtaining an average of 32 million reads per library, we show that the presence of numerous nuclear G4C2 repeat RNA foci does not cause extensive changes in RNA processing in this model organism. Comparision of the transcriptomic profile of flies expressing 5R or 160R from two different chromosomes

2015-09-11 | E-GEOD-72771 | biostudies-arrayexpress

Differential Toxicity of Nuclear RNA Foci Versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS

2015-09-11 | GSE72771 | GEO

Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice.

Project description:A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy.

| S-EPMC4828340 | biostudies-literature

Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

Project description:G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/Igf signalling is reduced in fly models of C9orf72 repeat expansion using RNA-sequencing of adult brain. We further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/Igf signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.

2021-03-20 | GSE151826 | GEO

A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD

Project description:An abnormal expansion of a G4C2 hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we developed a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits. This high-fidelity system possessed improved transcriptome-wide specificity compared to its native form and mediated targeting in motor neuron-like cells derived from a patient with ALS. These results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.

2024-11-28 | GSE251822 | GEO

A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD

2024-11-28 | GSE250633 | GEO

C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD

Project description:Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (~100–1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients.

2016-02-10 | GSE77720 | GEO

C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD

Project description:Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (~100â??1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients. To compare the RNA Seq profiles from the cortex and spinal cord of transgenic mice expressing unexpanded human C9orf72 (F08, n=4), expanded human C9orf72 (F112, n=3/4), and nontransgenic controls (n=4).

2016-02-10 | E-GEOD-77720 | biostudies-arrayexpress

Identification of proteins interacting with GFP-GA, GR, PA, PG and PR fusion proteins

Project description:Expansion of a hexanucleotide repeat GGGGCC (G4C2) in C9ORF72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. Transcripts carrying (G4C2) expansions undergo unconventional, non-ATG-dependent translation, generating toxic dipeptide repeat (DPR) proteins that are thought to contribute to disease. Here, we transfected HEK 293T cells with GFP-tagged dipeptides (GA, GR, PA, PG and PR) and performed LC-MS/MS to identify immunoprecipitated interactors.

2016-10-03 | PXD004938 | Pride

Gene expression signatures for Normal-looking, fibrotic foci and hyperplastic (adjacent to fibrotic foci) area in IPF lungs

Project description:To further understand the pathologic microenvironment in IPF, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish normal and IPF lung in normal-looking, fibrotic foci and hyperplastic areas of IPF lung. Four IPF lungs were dissected into normal-looking, fibrotic foci and hyperplastic areas by Laser-Capture-Microdissection. Gene expression analysis showed that 638 significantly different genes were identified that clearly distinguished the different IPF microenvironments . Among them, MMP19 was revealed as one of the most significantly up-regulated genes that distinguished normal looking epithelial cells (N) to hyperplastic epithelial cells, MMP19 up-regulation in IPF lungs was verified by immunohistochemical (IHC), qRT-PCR and Western-blot. IPF lungs are heterogeneity complex, which comprise normal looking area, fibrotic foci and hyperplastic area. In this study we separated the normal, fibrotic foci and hyperplastic area by LCM and employed Agilent whole genome gene expression microarray profiling to identify genes with the potential to distinguish the unique microenironment of IPF

2013-01-11 | E-GEOD-35309 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data