C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project
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ABSTRACT:
PROVIDER: PRJNA497345 | ENA |
REPOSITORIES: ENA
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Project description:C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project
| PRJNA497344 | ENA
Project description:The involvement of microglia and neuroinflammation in amyotrophic lateral sclerosis (ALS) is well recognized, but the precise underlying molecular mechanisms remain elusive. We generated single-nuclei transcriptomic profiles from the spinal cord and motor cortex of sporadic (sALS) and C9orf72 (C9-ALS) ALS patients. We confirmed that C9orf72 is highly expressed in microglia and observed that the hexanucleotide repeat expansion (HRE) results in haploinsufficiency specifically in these cells. Whereas sALS microglia transitioned towards classically defined disease-associated transcriptomic profiles, C9orf72 HRE microglia exhibited a diminished response, with alterations in phagocytic and lysosomal pathways. We confirmed these observations using a human microglia xenograft model, which showed that C9orf72 loss-of-function leads to a reduced baseline activation, with lower expression of antigen-presenting related genes. We also confirmed the alterations in the endolysosomal pathway in C9orf72-HRE and C9orf72-deficient induced pluripotent stem cell (iPSC)-derived microglia. In addition, we observed a diminished response of astrocytes in C9orf72-HRE carriers and provided an extensive map of dysregulated ligand-receptor pairs in microglia and astrocyte indicating an altered cell-cell communication in both C9orf72 and sALS. This complex cellular interplay highlights variations in the cellular substrate of sporadic and inherited forms of ALS, providing valuable insights for patient stratification and for selecting appropriate treatments.
2025-10-20 | GSE302319 | GEO
Project description:The involvement of microglia and neuroinflammation in amyotrophic lateral sclerosis (ALS) is well recognized, but the precise underlying molecular mechanisms remain elusive. We generated single-nuclei transcriptomic profiles from the spinal cord and motor cortex of sporadic (sALS) and C9orf72 (C9-ALS) ALS patients. We confirmed that C9orf72 is highly expressed in microglia and observed that the hexanucleotide repeat expansion (HRE) results in haploinsufficiency specifically in these cells. Whereas sALS microglia transitioned towards classically defined disease-associated transcriptomic profiles, C9orf72 HRE microglia exhibited a diminished response, with alterations in phagocytic and lysosomal pathways. We confirmed these observations using a human microglia xenograft model, which showed that C9orf72 loss-of-function leads to a reduced baseline activation, with lower expression of antigen-presenting related genes. We also confirmed the alterations in the endolysosomal pathway in C9orf72-HRE and C9orf72-deficient induced pluripotent stem cell (iPSC)-derived microglia. In addition, we observed a diminished response of astrocytes in C9orf72-HRE carriers and provided an extensive map of dysregulated ligand-receptor pairs in microglia and astrocyte indicating an altered cell-cell communication in both C9orf72 and sALS. This complex cellular interplay highlights variations in the cellular substrate of sporadic and inherited forms of ALS, providing valuable insights for patient stratification and for selecting appropriate treatments.
2025-10-20 | GSE302295 | GEO
Project description:C9orf72 hexanucleotide repeat expansions impair microglial response in models of ALS
| PRJNA1289862 | ENA
Project description:Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila
| PRJNA637376 | ENA
Project description:A hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. While repeat RNAs are implicated in disease pathogenesis, their mechanisms of actions remain incompletely understood. Here we show that GGGGCC repeat RNA engages chromatin genome-wide preferentially at promoter regions in patient cells. This interaction obstructs RNA polymerase II and transcription factors with GC-rich motifs, leading to broad transcriptional repression. Biochemical assays, single-molecule imaging, and native bisulfite sequencing analyses demonstrate that GGGGCC repeat RNA intrinsically forms DNA:RNA hybrid G-quadruplexes with cognate DNA, providing a structural basis for transcriptional interference. Stabilization of these G-quadruplex structures exacerbates neuronal vulnerability to metabolic stress in patient-derived motor neurons and cortical organoids, whereas restoring key gene dysregulation improves neuronal resistance to stress. These findings uncover a previously unrecognized trans-acting mechanism whereby repetitive RNAs form hybrid structures with genomic DNA, disrupt gene regulation, and contribute to neurodegeneration.
2026-02-24 | GSE310930 | 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: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:A hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. While repeat RNAs are implicated in disease pathogenesis, their mechanisms of actions remain incompletely understood. Here we show that GGGGCC repeat RNA engages chromatin genome-wide preferentially at promoter regions in patient cells. This interaction obstructs RNA polymerase II and transcription factors with GC-rich motifs, leading to broad transcriptional repression. Biochemical assays, single-molecule imaging, and native bisulfite sequencing analyses demonstrate that GGGGCC repeat RNA intrinsically forms DNA:RNA hybrid G-quadruplexes with cognate DNA, providing a structural basis for transcriptional interference. Stabilization of these G-quadruplex structures exacerbates neuronal vulnerability to metabolic stress in patient-derived motor neurons and cortical organoids, whereas restoring key gene dysregulation improves neuronal resistance to stress. These findings uncover a previously unrecognized trans-acting mechanism whereby repetitive RNAs form hybrid structures with genomic DNA, disrupt gene regulation, and contribute to neurodegeneration.
2026-02-24 | GSE310926 | GEO
Project description:A hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. While repeat RNAs are implicated in disease pathogenesis, their mechanisms of actions remain incompletely understood. Here we show that GGGGCC repeat RNA engages chromatin genome-wide preferentially at promoter regions in patient cells. This interaction obstructs RNA polymerase II and transcription factors with GC-rich motifs, leading to broad transcriptional repression. Biochemical assays, single-molecule imaging, and native bisulfite sequencing analyses demonstrate that GGGGCC repeat RNA intrinsically forms DNA:RNA hybrid G-quadruplexes with cognate DNA, providing a structural basis for transcriptional interference. Stabilization of these G-quadruplex structures exacerbates neuronal vulnerability to metabolic stress in patient-derived motor neurons and cortical organoids, whereas restoring key gene dysregulation improves neuronal resistance to stress. These findings uncover a previously unrecognized trans-acting mechanism whereby repetitive RNAs form hybrid structures with genomic DNA, disrupt gene regulation, and contribute to neurodegeneration.
2026-02-24 | GSE310928 | GEO