Partial depletion of SRSF1 rescued the C9ORF72-repeat neurodegeneration-associated locomotor deficits in G4C2x36 Drosophila lines
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PROVIDER: PRJNA576478 | ENA |
REPOSITORIES: ENA
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Project description:In this study we investigated the role of SRSF1 in mitigating locomotor defect in C9ORF72-ALS/FTD Drosophila lines. We analysed the transcriptomes of Drosophila heads from the same lines: (i) control flies expressing 3 G4C2 repeats and a luciferase-RNAi control (G4C2x3 + C-RNAi); (ii) C9ORF72-ALS/FTD model expressing 36 G4C2 repeats and the RNAi control (G4C2x36 + C-RNAi); (iii) C9ORF72-ALS/FTD-neuroprotected flies expressing 36 G4C2 repeats and the disrupted SRSF1 allele (G4C2x36 + ΔSRSF1). RNA samples were profiled using Drosophila 3' IVT gene expression Affymetrix microarrays prior to qRT-PCR validation of the SRSF1 depletion in neuroprotected flies. This study is part of a larger study that investigates the mitigating role of SRSF1 at whole-genome level to detect transcriptomal alterations and neuronal hyperexcitability in C9ORF72-linked amyotrophic lateral sclerosis.
2021-07-21 | GSE138592 | GEO
Project description:Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to relentless paralysis and death usually within a few years from symptom onset. Thousands of RNA molecules with roles in multiple cellular pathways are compromised in disease challenging the identification of alterations causing pathogenesis over downstream changes consequent to neurodegeneration. We recently showed that partial depletion of SR-rich splicing factor SRSF1 inhibits the nuclear export of pathological C9ORF72-repeat transcripts and subsequent translation of dipeptide-repeat proteins in patient-derived neurons and Drosophila, providing in turn a promising strategy of neuroprotection for the most common form of ALS. While the roles of SRSF1 remain poorly characterised in neurons, its therapeutic manipulation offers a rare opportunity to identify disease-modifying gene expression changes. Here, we report diseased and neuroprotected transcriptomes from human-derived neurons and Drosophila heads. Strikingly, while the depletion of SRSF1 has limited effects on genome-wide expression, splicing and nuclear export of RNAs, reversal of 90 disease-modifying transcripts were identified over 2,000 RNA changes in human disease. Functional validation further demonstrated that conserved potassium intermediate/small conductance calcium-activated KCNN channel inhibitors mitigate C9ORF72-ALS mediated hyperexcitability and death of human motor neurons as well as Drosophila motor deficits. Our data support efficacy and safety of SRSF1 manipulation as a therapeutic approach leading to rescue of multiple biological processes without disrupting neuronal transcriptomes. In addition to a potential new therapeutic target for pharmacological inhibition, we also identified in vitro and in vivo disease-modifying gene expression signatures to guide the development of new biomarkers and novel therapeutic approaches in C9ORF72-ALS/FTD.
2021-07-19 | GSE139900 | GEO
Project description:Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays. We further demonstrate that either depleting SRSF1 or preventing its interaction with NXF1 specifically inhibits the nuclear export of pathological C9ORF72 transcripts, the production of dipeptide-repeat proteins and alleviates neurotoxicity in Drosophila, patient-derived neurons and neuronal cell models. Taken together, we show that repeat RNA-sequestration of SRSF1 triggers the NXF1-dependent nuclear export of C9ORF72 transcripts retaining expanded hexanucleotide repeats and reveal a novel promising therapeutic target for neuroprotection.
| S-EPMC5504286 | biostudies-literature
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 | GSE203578 | GEO
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 | GSE203580 | GEO
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
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
Project description:The p52 isoform of Psip1/Ledgf links histone H3K36 methylation and the regulation of alternative splicing. Chromatin immunoprecipitation (ChIP) of Psip1 together with H3K36me3 and Srsf1 and by ChIP-on-chip analysis demonstrated that H3K36me3, Psip1 and SRSF1 enrichment correlates on the gene bodies Array design includes 2 dye swap replicates for Srsf1 and Psip1-/- samples, and single arrays for PSIP and H3K36me3 samples
2012-01-01 | E-GEOD-31520 | biostudies-arrayexpress
Project description:we report insulin secretion defects in SRSF1 Ins2-Cre mice, in which SRSF1 is ablated in pancreatic β cells.
2023-04-17 | GSE173455 | GEO