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P53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)

ABSTRACT: p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)

PROVIDER: PRJNA680362 | ENA |

REPOSITORIES: ENA

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p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)

Project description:To analyze the epigenomic landscape of neurodegeneration caused by ALS-associated protein aggregation, we developed a modified version of ATAC-seq that works on primary neurons. We discovered that C9orf72-ALS/FTD associated poly(PR) activated a remarkably specific signature of chromatin accessibility, involving transcriptional targets of the tumor suppressor gene p53. Our findings reveal an unexpected role of p53 as a mediator of neurodegeneration elicited by poly(PR) and provide an example of how ATAC-seq can now be applied to neurons to define mechanisms of neurodegeneration.

2020-12-09 | GSE162048 | GEO

Translation deficits drive C9orf72 associated poly-GR/PR toxicity

Project description:Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients with the C9orf72 mutation show predominantly cytoplasmic aggregates of poly-GR and poly-PR proteins that are acutely toxic in various model systems. To identify the molecular mediators of neurotoxicity of poly-GR/PR, we analyzed their interactomes in primary neurons. GFP-(GR)149 and (PR)175-GFP preferentially interacted with RNA-binding proteins, including stress granule-associated and nucleolar proteins, as well as ribosomes. Overexpression of the poly-GR/PR interactors Staufen 1/2 (STAU1/2) and YBX1 led to cytoplasmic aggregation of poly-GR/PR into large stress granule-like inclusions, while the poly-GR/PR interactor nucleophosmin (NPM1) recruited poly-GR into the nucleolus. In addition, poly-PR expression reduced ribosome levels and translation, which is consistent with the widespread reduction of synaptic proteins detected by proteomics. Surprisingly, only GFP-(GR)53, but not GFP-(GR)149, localized to the nucleolus and reduced ribosome levels and translation in neurons, suggesting impaired ribosome biogenesis is driving the acute toxicity commonly observed in vitro. In C9orf72 patient brains, we detected co-aggregation of poly-GR/PR inclusions with ribosomes, but not stress granules. Partial sequestration of ribosomes may chronically impair protein synthesis and contribute to C9orf72 ALS/FTD pathogenesis.

2018-06-27 | PXD008691 | Pride

Transcriptome-wide RNA binding analysis of C9orf72 poly(PR) dipeptides

Project description:An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeats are transcribed in both sense and antisense directions to generate distinct dipeptide repeat proteins, of which poly(GA), poly(GR) and poly(PR) have been implicated in contributing to neurodegeneration. Poly(PR) binding to RNA may contribute to toxicity, but analysis of poly(PR)-RNA binding on a transcriptome-wide scale has not yet been carried out. We therefore performed crosslinking and immunoprecipitation (CLIP) analysis in human cells to identify the RNA binding sites of poly(PR). We found that poly(PR) binds to nearly 600 RNAs, with the sequence GAAGA enriched at the binding sites. In vitro experiments showed that poly(GAAGA) RNA binds poly(PR) with higher affinity than control RNA and induces phase-separation of poly(PR) into condensates. These data indicate that poly(PR) preferentially binds to poly(GAAGA)-containing RNAs, which may have physiological consequences.

2023-07-10 | GSE212761 | GEO

p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR).

Project description: Not available

| S-EPMC7886018 | biostudies-literature

Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR

Project description:Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR

| PRJNA545960 | ENA

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

Project description: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.

2019-05-29 | GSE124834 | GEO

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

Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR.

Project description: Not available

| S-EPMC6606620 | biostudies-literature

Proteomics and C9orf72 neuropathology identify ribosomes as poly-GR/PR interactors driving toxicity.

Project description: Not available

| S-EPMC6238541 | biostudies-literature

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

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