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Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Fen-Biao Gao

PROVIDER: E-GEOD-72771 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2015-09-11 | GSE72771 | GEO

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

Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS

Project description:Dysregulation of RNA processing contributes to neurodegenerative diseases, especially amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common cause of both FTD and ALS (C9-FTD/ALS), characterized with aberrant repeat RNA foci in the nucleus and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions in the cytoplasm. Here we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon-skipping and intron retention in human iPSC-derived neurons. Similar alternative splicing changes can be found in patient postmortem tissues. This work identified novel molecular mechanism of global RNA splicing defects by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.

2024-08-23 | GSE248404 | GEO

N6-methyladenosine regulates RNA metabolism and neurodegeneration in C9ORF72-ALS/FTD [seq_polyA_RNA-decay]

Project description:N6-methyladenosine (m6A) is the most prevalent internal mRNA modification and regulates RNA metabolism. Repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Here, we showed that m6A is downregulated in C9ORF72-ALS/FTD patient-derived iPSC-differentiated neurons and postmortem brain tissues. The global m6A hypomethylation leads to transcriptome-wide mRNA stabilization and upregulated gene expression, especially ones involved in synaptic activity and neuronal functions. The m6A modification in the C9ORF72 intron sequence preceding the expanded repeats enhances RNA degradation via the nuclear reader YTHDC1. The m6A reduction leads to increased accumulation of repeat RNA and poly-dipeptides. Moreover, the antisense RNA can also be regulated by m6A. Elevating m6A level significantly reduces both sense and antisense repeat RNA and poly-dipeptides, rescues global mRNA homeostasis, and improves survival of C9ORF72-ALS/FTD patient neurons.

2023-06-09 | GSE203579 | GEO

N6-methyladenosine regulates RNA metabolism and neurodegeneration in C9ORF72-ALS/FTD [seq_polyA_RNA-RIP]

2023-06-09 | GSE203578 | GEO

N6-methyladenosine regulates RNA metabolism and neurodegeneration in C9ORF72-ALS/FTD [seq_total_RNA-MeRIP]

2023-06-09 | GSE203580 | GEO

Characterising day 90 human C9ORF72-ALS/FTD cerebral organoids at single cell level

Project description:A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human imaging and experimental studies hint at early changes in the brain in C9-ALS/FTD, which remain poorly understood. To define these changes, we used cerebral organoid models derived from C9-ALS/FTD patients and controls to create a single cell RNA sequencing dataset at day 90. Together, these dataset will help to shed light on initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.

2024-09-06 | GSE264012 | 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

Poly-GR impairs translation elongation and increases ribotoxic stress response in C9ORF72-ALS/FTD

Project description:Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Poly-GR is one of the most toxic dipeptide repeat (DPR) proteins translated from the RNA repeats. It has been shown to affect protein synthesis, but how this contributes to neurodegeneration is not clear. Here, we found that poly-GR inhibits global translation by perturbing translation elongation. We identified that the transcripts with relatively slow elongation rate tend to be further stalled by poly-GR in iPSC-differentiated neurons. This increases ribosome collision and ZAKα-mediated ribotoxic stress response (RSR), which elevates the phosphorylation of p38 and promotes cell death. Knockdown of ZAKα or pharmacological inhibition of p38 can ameliorate the GR toxicity, and improve the survival of C9ORF72-ALS/FTD patient-derived iPSC-neurons. Our study reveals molecular mechanism of poly-GR mediated toxicity on global translatome, and identifies RSR as a potential therapeutic target for C9ORF72-ALS/FTD.

2024-08-23 | GSE230127 | 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

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