Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

ABSTRACT: Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

PROVIDER: PRJNA637376 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Similar Datasets

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

C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project

Project description:C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project

| PRJNA497345 | ENA

C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project

Project description:C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project

| PRJNA497344 | ENA

Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in <i>Drosophila</i>.

Project description: Not available

| S-EPMC8007214 | biostudies-literature

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9orf72 dipeptide repeat protein toxicity

Project description:Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9FTD/ALS). The nucleotide repeat expansions are translated into dipeptide repeat (DPR) proteins, which are aggregation-prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene knockout screens for suppressors and enhancers of C9orf72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA processing pathways, and in chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9orf72 DPRs in neurons, and improved survival of human induced motor neurons from C9orf72 ALS patients. Together, this work demonstrates the promise of CRISPR-Cas9 screens to define mechanisms of neurodegenerative diseases. This dataset contains the RNA-sequencing data used to support the conclusions from this study.

2018-02-27 | GSE109177 | GEO

Correction of ALS-related phenotypes in iPSC-derived motor neurons carrying a hexanucleotide expansion mutation in C9orf72 by CRISPR/Cas9 genome editing and homology-directed repair

Project description:The G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number of different methods have been used in an attempt to generate isogenic control lines using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 and NHEJ by deleting the repeat region without replacing it with the normal repeat size, but typically this strategy carries the risk of creating indels and genomic instability. In this study we demonstrate complete correction of an induced pluripotent stem cell (iPSC) line derived from a C9orf72-HR positive ALS patient using CRISPR/Cas9 genome editing and homology directed repair (HDR), resulting in replacement of the excised region with a donor template carrying the wild-type repeat size to maintain the genetic architecture of the locus. The isogenic correction of the C9orf72 HRE restored normal expression and methylation at the C9orf72 locus, reduced intron retention in the edited lines, and abolished pathological phenotypes associated with the C9orf72 HRE expansion in iPSC derived motor neurons (iPSMNs). RNA sequencing of the mutant line identified 2220 differentially expressed genes compared to its isogenic control. Enrichment analysis demonstrated an over-representation of ALS relevant pathways in the presence of the C9orf72 HRE, including calcium ion dependent exocytosis, synaptic transport and the KEGG ALS pathway, as well as new targets of potential relevance to ALS pathophysiology.Complete correction of the C9orf72 HRE in iPS MNs by CRISPR/Cas9 mediated HDR provides an ideal model to study the earliest effects of the hexanucleotide expansion on cellular homeostasis and the key pathways implicated in ALS pathophysiology.

2020-05-19 | GSE139144 | GEO

C9ORF72 repeat expansion affects the proteome of primary skin fibroblasts in ALS and FTD

Project description:The study design involves the proteomics characterization of primary skin fibroblast cell lines derived from skin biopsies from patients affected by either amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). Patients enrolled were divided in three groups: 1) ALS patients carrying the C9ORF72 repeat expansion as main genetic mutation (c9orf72 pos; n=6), 2) sporadic ALS patients, carrying mutations other than the C9ORF72 repeat expansion (c9orf72 neg; n=8), 3) FTD patients carrying the C9ORF72 repeat expansion (FTD; n=2). Total protein extracts were obtained from primary skin fibroblasts cultures and trypsin digested. Shotgun proteomics by LC-MS/MS (two technical replicates per sample) and systems biology analyses were performed as follows

2021-11-02 | PXD023866 | Pride

Profiling nucleo/cytoplasmic distribution of mRNAs identifies a role for the Golgi-to-ER trafficking in C9orf72 toxicity

Project description:Compelling evidence indicates that defects in nucleocytoplasmic transport contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). In particular, hexanucleotide (G4C2) repeat expansions in C9orf72, the most common cause of genetic ALS, have a widespread impact on the transport machinery that regulates the nucleocytoplasmic distribution of proteins and RNAs, thereby affecting their functions. We have previously reported that the expression of G4C2 hexanucleotide repeats in cultured human and mouse cells caused a marked accumulation of poly(A) mRNAs in cell nuclei, suggesting that mRNA trafficking is impaired by expanded C9orf72-ALS repeats. To further characterize the process, in this work we set out to systematically identify the specific mRNAs that are altered in their nucleocytoplasmic distribution in the presence of C9orf72-ALS repeats. Results from RNAseq profiling of nuclear and cytoplasmic RNA fractions obtained from cells expressing G4C231 repeats show a significant accumulation of mRNAs in the nuclei of G4C231 cells, further suggesting that nuclear retention of mRNAs is a major effect of C9orf72 expanded repeats expression. Interestingly, pathway analysis shows that mRNAs involved in ER-to-Golgi trafficking are particularly enriched among the identified mRNAs. Most importantly, functional studies in cultured cells and Drosophila indicate that the membrane trafficking route regulated by ARFGAP1, a GTPase-activating protein that associates with Golgi, is specifically affected by expanded C9orf72 repeats, as well as by C9orf72-related dipeptide repeat proteins (C9-DPRs), pointing to ER-to-Golgi vesicle-mediated transport as a target of C9orf72 toxicity.

2023-08-21 | GSE235448 | GEO

The C9ORF72 Repeat Epansion Impairs Neurodevelopment

Project description:RNA sequencing analysis of human iPSC-derived neural stem cells generated from Control, C9ORF72 FTD/ALS, an isogenic control, and a C9ORF72 knockout line. The goal of this study is to determine the effects of the C9ORF72 repeat expansion on neural stem cell proliferation and differentiation.

2023-08-12 | GSE238005 | GEO

Knocking out C9ORF72 exacerbates axonal trafficking defects associated with hexanucleotide repeat expansion and reduces levels of heat shock proteins I

Project description:iPSCs with mutant C9ORF72 were edited using CRISPR/Cas9 (1) to knockout C9ORF72 or, alternatively, (2) to correct the ALS mutation, followed by differentiation into motor neurons.

2020-01-17 | GSE143743 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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