A chemical screen identifies compounds limiting the toxicity of C9ORF72 dipeptide repeats [drug treatment]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA478380 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7448500.fastq.gz | Fastqsanger.gz | |||
| SRR7448501.fastq.gz | Fastqsanger.gz | |||
| SRR7448502.fastq.gz | Fastqsanger.gz | |||
| SRR7448497.fastq.gz | Fastqsanger.gz | |||
| SRR7448498.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 6 |
Similar Datasets
Project description:A chemical screen identifies compounds limiting the toxicity of C9ORF72 dipeptide repeats
| PRJNA434079 | ENA
Project description:Purpose: Compare the effect of PR20 alone or together with PFI or NaPhen Methods: NSC-34 cells are wildtype in the non-coding hexanucleotide repeat status of C9orf72. NSC-34 cell cultures were treated with PR20, PFI or NaPhen alone for 48 hours, or in combination (48 hours with PR20 and the last 24 hours with PFI or NaPhen). mRNA profiles of the different conditions were generated by RNAseq. Sequencing reads were aligned and analyzed for differential gene expression. Results: The analysis reveals that the transcriptional changes induced by PR20 are alleviated by the treatment with PFI or NaPhen.
2021-06-26 | GSE116392 | GEO
Project description:Purpose: Compare parental NSC34 cells with NSC34 PR20-resistant clones Methods: NSC-34 cell cultures were treated with PR20, a peptide that contains 20 copies of Proline-Arginine aminoacids, for two weeks. mRNA profiles of resistant clones were generated by RNAseq. Sequencing reads were aligned and analyzed for differential gene expression. Results: NSC34 clones that gained spontaneous resistance to PR20 present a higher levels of translation than parental cells. Gene Set Enrichment Analysis (GSEA) of this dataset revealed an overall upregulation of factors from the “mTORC1 signaling” hallmark
2021-02-14 | GSE110596 | GEO
Project description:Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson’s disease patients, but the association was not found in autopsy confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson’s but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n=354 cases, odds ratio=3.59, p-value=0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.
2019-09-17 | GSE133323 | GEO
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
Project description:Liquid-liquid phase separation (LLPS) of RNA binding proteins underlies the formation of multiple membraneless organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a corner stone of ALS/FTLD pathogenesis. Phase separation of ALS-linked stress granule proteins has been shown to rely on hydrophobic interactions. Here we identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS, and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. In the present proteomics experiment, we wondered which cellular proteins could interact with synthetic PR30 peptide. We took soluble HeLa cell lysate, to which we added increasing concentrations of PR30. The PR30 peptide spontaneously demixed, and could be separated from the solution by gentle centrifugation. Unexpectedly, the resulting pellet was largely resistant to washing steps, suggesting that PR induced the precipitation of different cellular proteins to the insoluble fraction. To see whether weak interactions could still be involved in the process, we also performed mild crosslinking with paraformaldehyde. Mass-spectroscopy (MS) analysis on both crosslinked and uncrosslinked samples identified 874 proteins that were detected and quantified in both conditions.
2017-04-26 | PXD005509 | Pride
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
Project description:Repeat expansions in the C9orf72 gene are a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two devastating neurodegenerative disorders. One of the proposed mechanisms of GGGGCC repeat expansion is their translation to produce unnatural dipeptide repeat (DPR) proteins that accumulate in aggregates and contribute to the pathology. There are 5 different DPRs poly(GA), poly(GR), poly(PR), poly(PA), poly(GP) which are neurotoxic in vitro. In our study, we identified the interactome of all five DPR proteins, consisting of 125 repeats, overexpressed in HEK293T cells using BioID2 proximity labeling. We identified 140 interacting partners for polyGR, 130 for polyGA, 138 for polyPR, 62 for polyPA, and 38 for polyGP. Gene ontology enrichment analysis of proteomic data identified interaction candidates involved in protein translation, signal transduction pathways, protein catabolic processes, amide metabolic processes, and RNA-binding. Through further analyses, we evaluated the interaction between polyGA and Valosin-containing protein (VCP) in HEK293T cells as well as in brains of C9orf72 patients. Furthermore, we are showing that polyGA sequester VCP in polyGA aggregates and hinders its function. Additionally, we analyzed the effect of decreased level of VCP on autophagic markers p62 and LC3.
2022-05-19 | PXD024120 | Pride
Project description:Profiling of proximity proteomes of C9orf72-derived dipeptide repeat proteins (poly-GA, poly-GR, poly-PR) in HEK293 cells using BioID assay
2021-12-17 | MSV000088581 | MassIVE
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