Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Toxic C9orf72 poly(PR) binds heterochromatin, disrupts HP1α and causes dsRNA accumulation

ABSTRACT: How G4C2 repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. Here, we report the first mouse model to express poly(PR), a dipeptide repeat protein synthesized from expanded G4C2 repeats. Expression of GFP-(PR)50 throughout the mouse brain yielded progressive brain atrophy, neuron5 loss, loss of poly(PR)-positive cells and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused abnormal histone methylation, lamin invaginations, decreases in HP1α expression, and disruptions of HP1α liquid phases. These aberrations of histone methylation, lamins and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element10 expression and double-stranded RNA accumulation. Thus, we uncover new mechanisms by which poly(PR) contributes to c9FTD/ALS pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE124834 | GEO | 2019/05/29

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Toxic C9orf72 poly(PR) binds heterochromatin, disrupts HP1α and causes dsRNA accumulation

Project description:Toxic C9orf72 poly(PR) binds heterochromatin, disrupts HP1α and causes dsRNA accumulation

| PRJNA513973 | ENA

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 heterochromatin gene signature unveils HP1α mediating neuroendocrine prostate cancer development and aggressiveness

Project description:Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) with hyperchromatic nuclei being a distinguishing histopathological feature. Here we show that, underlying this distinct nuclear structure, heterochromatin related genes are significantly enriched in NEPC. Among them, heterochromatin protein 1α (HP1α) expression is increased early in NE transdifferentiation and is consistently elevated in clinical NEPC samples. Functional studies showed that HP1α knockdown attenuates NEPC tumor growth by inhibiting proliferation and survival. Its ectopic expression significantly promotes NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. To identify mechanisms underlying the function of HP1α involved in NEPC cell proliferation and adenocarcinoma cell NE transdifferentiation, we analyzed gene expression profiles from stable NEPC cell lines with control or HP1α knockdown, and adenocarcinoma cell lines with control or HP1α overexpression, respectively.

2018-01-22 | GSE105033 | GEO

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

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

Project description: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.

2015-11-14 | GSE74973 | GEO

RNA sequencing of human fibroblasts after SUPT4H1 siRNA treatment

Project description:Asses the transcriptome-wide changes associated with depletion of transcription elongation factor, SUPT4H1, in human fibroblasts. An expanded hexanucleotide repeat in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9FTD/ALS). Therapeutics (e.g., antisense oligonucleotides) are being developed to target RNAs containing the expanded repeat sequence (GGGGCC); however, this approach is complicated by the presence of antisense strand transcription of expanded GGCCCC repeats. We found that targeting the transcription elongation factor, Spt4, selectively decreased production of both sense and antisense expanded transcripts, as well as their translated dipeptide repeat (DPR) products, and also mitigated degeneration in animal models. Inhibition of SUPT4H1, the human ortholog of Spt4, similarly decreased production of sense and antisense RNA foci as well as DPR proteins in c9ALS patient fibroblasts and neurons from patient-derived induced pluripotent stem cells, consistent with our finding that cerebellar DPR protein levels correlate with SUPT4H1 expression in c9FTD/ALS patients. Therapeutic targeting of a single factor to eliminate pathological features of c9FTD/ALS offers advantages over approaches that require targeting sense and antisense repeats separately.

2016-09-09 | GSE83484 | GEO

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

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

2015-09-11 | GSE72771 | GEO

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

Proximity proteomics of C9orf72 dipeptide repeat proteins

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

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