RNA Sequencing of induced pluripotent stem cell derived motor neurons from C9orf72 hexanucleotide repeat expansion carriers and controls
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE233261 | GEO | 2025/05/01
REPOSITORIES: GEO
Similar Datasets
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:Importance: An intronic hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest monogenic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Predicting those who will develop neurodegeneration and its timing will be essential to initiating and assessing preventative therapy. This requires consideration of both compensatory, protective mechanisms and pathogenic events prior to overt neurodegeneration. Objective: To identify biochemical changes in individuals at higher risk of developing ALS or FTD via C9orf72 HRE heterozygosity. Design: Cross sectional observational study. Setting: Tertiary ALS or dementia referral centre. Participants: People with established ALS or FTD, either due to C9orf72 HRE or apparently sporadic cases; asymptomatic first-degree relatives of those with a known C9orf72 HRE; asymptomatic non-carrier controls. Exposure: C9orf72 HRE. Main outcomes: Relative abundance of 30 predefined cerebrospinal fluid biomarkers of ALS and FTD comparing asymptomatic C9orf72 HRE carriers and age-matched non-carriers. Differential abundance of proteins quantified using data independent acquisition mass spectrometry and neurofilament light chain measured by electrochemiluminescent assay. Results: Data for 19 people with sporadic ALS, 10 people with C9orf72 ALS, 14 people with sporadic FTD, 10 people with C9orf72 FTD, 48 asymptomatic C9orf72 HRE carriers and 39 non-carrier controls were analysed. Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value = 0.034). Neurofilament light chain levels did not differ significantly between groups. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after exclusion of those with high neurofilament light chain levels, after adjusting for NFL level and after adjusting for age. Conclusions and relevance: Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 hexanucleotide repeat expansion carriers occurs in the absence of elevation in neurofilament light chain, potentially reflecting mechanisms that precede the phase of neurodegeneration characterised by rapid neuronal loss. Such mechanisms may have either compensatory or pathogenic roles. Ubiquitin carboxyl-terminal hydrolase isozyme L1 elevation brings forward the window on the changes associated with the C9orf72 HRE carrier state, with the potential to inform understanding penetrance and approaches to prevention.
2024-11-19 | PXD051859 | Pride
Project description:C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project
| PRJNA497344 | ENA
Project description:C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project
| PRJNA497345 | ENA
Project description:Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. We report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased, leading to accumulation of GGGGCC repeat–containing RNA foci selectively in C9-ALS iPSC-derived motor neurons. Repeat-containing RNA foci colocalized with hnRNPA1 and Pur-?, suggesting that they may be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS. Transcriptome profiling from iPSC derived motor neurons compared to controls
2013-11-07 | E-GEOD-52202 | biostudies-arrayexpress
Project description:RNA Sequencing of induced pluripotent stem cell derived motor neurons from C9orf72 hexanucleotide repeat expansion carriers and controls
| PRJNA975581 | ENA
Project description:Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. We report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased, leading to accumulation of GGGGCC repeat–containing RNA foci selectively in C9-ALS iPSC-derived motor neurons. Repeat-containing RNA foci colocalized with hnRNPA1 and Pur-α, suggesting that they may be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS.
2013-11-07 | GSE52202 | GEO
Project description:The G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number of different methods have been used in an attempt to generate isogenic control lines using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 and NHEJ by deleting the repeat region without replacing it with the normal repeat size, but typically this strategy carries the risk of creating indels and genomic instability. In this study we demonstrate complete correction of an induced pluripotent stem cell (iPSC) line derived from a C9orf72-HR positive ALS patient using CRISPR/Cas9 genome editing and homology directed repair (HDR), resulting in replacement of the excised region with a donor template carrying the wild-type repeat size to maintain the genetic architecture of the locus. The isogenic correction of the C9orf72 HRE restored normal expression and methylation at the C9orf72 locus, reduced intron retention in the edited lines, and abolished pathological phenotypes associated with the C9orf72 HRE expansion in iPSC derived motor neurons (iPSMNs). RNA sequencing of the mutant line identified 2220 differentially expressed genes compared to its isogenic control. Enrichment analysis demonstrated an over-representation of ALS relevant pathways in the presence of the C9orf72 HRE, including calcium ion dependent exocytosis, synaptic transport and the KEGG ALS pathway, as well as new targets of potential relevance to ALS pathophysiology.Complete correction of the C9orf72 HRE in iPS MNs by CRISPR/Cas9 mediated HDR provides an ideal model to study the earliest effects of the hexanucleotide expansion on cellular homeostasis and the key pathways implicated in ALS pathophysiology.
2020-05-19 | GSE139144 | GEO
Project description:Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila
| PRJNA637376 | ENA
Project description:The study design involves the proteomics characterization of primary skin fibroblast cell lines derived from skin biopsies from patients affected by either amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). Patients enrolled were divided in three groups: 1) ALS patients carrying the C9ORF72 repeat expansion as main genetic mutation (c9orf72 pos; n=6), 2) sporadic ALS patients, carrying mutations other than the C9ORF72 repeat expansion (c9orf72 neg; n=8), 3) FTD patients carrying the C9ORF72 repeat expansion (FTD; n=2). Total protein extracts were obtained from primary skin fibroblasts cultures and trypsin digested. Shotgun proteomics by LC-MS/MS (two technical replicates per sample) and systems biology analyses were performed as follows
2021-11-02 | PXD023866 | Pride