Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA279249 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1927020_1.fastq.gz | Fastqsanger.gz | |||
| SRR1927020_2.fastq.gz | Fastqsanger.gz | |||
| SRR1927030_1.fastq.gz | Fastqsanger.gz | |||
| SRR1927030_2.fastq.gz | Fastqsanger.gz | |||
| SRR1927040_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: The purpose of this experiment is to identify a C9-ALS/FTD specific genomic profile in fibroblast lines that is distinct from sporadic ALS without C9orf72 expansion and non-neurologic control cells. The study will then evaluate the effect on this identified profile of ASO treatment targeting the sense strand RNA transcript of the C9orf72 gene. Methods: Expression profiling was performed on RNAs from fibroblasts of four C9orf72 patients, four control individuals and four sporadic ALS patients using Multiplex Analysis of PolyA-linked Sequences method. Results: Hierarchical clustering of expression values for all genes showed that the four C9orf72 patient lines had an expression profile distinct from control and sporadic ALS lines. Statistical comparison of expression values between the four C9orf72 lines and the four control lines revealed that 122 genes were upregulated (defined by a False Discovery Rate FDR<0.05) and 34 genes were downregulated (defined by a False Discovery Rate FDR <0.05) in C9orf72 patient fibroblasts. Conclusions: A genome wide RNA signature can be defined in fibroblasts with C9orf72 expansion. ASO-mediated reduction of C9orf72 RNA levels in fibroblasts with the hexanucleotide expansion efficiently reduced accumulation of GGGGCC RNA foci. This did not, however, generate a reversal of the C9orf72 RNA profile. Use of Multiplex Analysis of PolyA-linked Sequences to identify expression changes in fibroblasts from amyotrophic lateral sclerosis and frontotemporal dementia patients harboring an hexanucleotide expansion in the C9orf72 gene.
2013-11-12 | E-GEOD-51684 | biostudies-arrayexpress
Project description:Increasing evidence suggests that defective RNA processing contributes to the development of amyotrophic lateral sclerosis (ALS). This may be especially true for ALS caused by a repeat expansion in C9orf72 (c9ALS), in which the accumulation of RNA foci and dipeptide-repeat proteins are expected to modify RNA metabolism. We report extensive alternative splicing (AS) and alternative polyadenylation (APA) defects in the cerebellum of c9ALS cases (8,224 AS, 1,437 APA), including changes in ALS-associated genes (e.g. ATXN2 and FUS), and cases of sporadic ALS (sALS; 2,229 AS, 716 APA). Furthermore, hnRNPH and other RNA-binding proteins are predicted as potential regulators of cassette exon AS events for both c9ALS and sALS. Co-expression and gene-association network analyses of gene expression and AS data revealed divergent pathways associated with c9ALS and sALS. Examination transcriptiome profiles in c9orf72-associated ALS, sporadic ALS and healthy control
2015-07-19 | E-GEOD-67196 | biostudies-arrayexpress
Project description:Purpose: The purpose of this experiment is to identify a C9-ALS/FTD specific genomic profile in fibroblast lines that is distinct from sporadic ALS without C9orf72 expansion and non-neurologic control cells. The study will then evaluate the effect on this identified profile of ASO treatment targeting the sense strand RNA transcript of the C9orf72 gene. Methods: Expression profiling was performed on RNAs from fibroblasts of four C9orf72 patients, four control individuals and four sporadic ALS patients using Multiplex Analysis of PolyA-linked Sequences method. Results: Hierarchical clustering of expression values for all genes showed that the four C9orf72 patient lines had an expression profile distinct from control and sporadic ALS lines. Statistical comparison of expression values between the four C9orf72 lines and the four control lines revealed that 122 genes were upregulated (defined by a False Discovery Rate FDR<0.05) and 34 genes were downregulated (defined by a False Discovery Rate FDR <0.05) in C9orf72 patient fibroblasts. Conclusions: A genome wide RNA signature can be defined in fibroblasts with C9orf72 expansion. ASO-mediated reduction of C9orf72 RNA levels in fibroblasts with the hexanucleotide expansion efficiently reduced accumulation of GGGGCC RNA foci. This did not, however, generate a reversal of the C9orf72 RNA profile.
2013-11-12 | GSE51684 | 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 | 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:We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive “multi-omic” analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis.
2017-08-14 | GSE97106 | GEO
Project description:Amyotrophic lateral sclerosis (ALS) is a deleterious neurodegenerative disease without effective treatment options. Recent studies have indicated the involvement of the dysregulation of RNA metabolism in the pathogenesis of ALS. Among the various RNA regulatory machineries, nonsense-mediated mRNA decay (NMD) is a stress responsive cellular surveillance system that degrades selected mRNA substrates to prevent the translation of defective or harmful proteins. Whether this pathway is affected in neurodegenerative diseases is unclear. Here we report that the NMD pathway is inhibited in ALS patients with C9orf72 hexanucleotide repeat expansion (HRE), the most common cause of familial ALS. Bioinformatic analysis of multiple transcriptome profiles revealed significant overlap of upregulated genes in NMD-defective cells with those in the brain tissues, micro-dissected motor neurons, or induced pluripotent stem cell-derived motor neurons from ALS patients carrying C9orf72 HRE, suggesting the suppression of NMD pathway in these patients. In contrast, there are few overlapping upregulated genes in brain tissues from sporadic ALS patients with those in NMD-defective cells. Using Drosophila models expressing various C9orf72 HRE products, we have validated the suppression of the NMD pathway by C9orf72 HRE and identified arginine-rich dipeptide repeats (DPRs) generated from HRE as the main culprits of NMD inhibition. Furthermore, in human SH-SY5Y neuroblastoma cells and in mouse brains, expression of arginine-rich DPRs was sufficient to cause NMD inhibition. Remarkably, expression of UPF1, a core gene in the NMD pathway, efficiently blocked neurotoxicity caused by arginine-rich DPRs in both cellular and Drosophila models. Although not as effective as UPF1, expression of another NMD gene UPF2 also ameliorated the degenerative phenotypes in DPR-expressing flies, indicating neuroprotection by genetically reactivating the NMD pathway. Finally, after validating Tranilast as an NMD-activating drug, we demonstrated its therapeutic potential in cellular and Drosophila models of C9orf72 DPR neurotoxicity. Therefore, our study has revealed the suppression of NMD in C9orf72 ALS and has suggested that the restoration of the NMD pathway by Tranilast, an asthma drug with solid safety record, could be a promising therapeutic strategy for ALS.
2018-12-01 | GSE123172 | GEO
Project description:Aims: Loss of nuclear TDP-43 characterises sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether 1) RNA splicing dysregulation is present in lower motor neurons in ALS and in a motor neuron-like cell model, and 2) TARDBP mutations (mtTARDBP) are associated with aberrant RNA splicing using patient-derived fibroblasts. Methods: Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurons obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. Findings were confirmed by qRT-PCR and in NSC34 motor neuronal cells following shRNA-mediated TDP-43 depletion. Exon arrays and immunohistochemistry were used to study mRNA splicing and TDP-43 expression in fibroblasts from patients with mtTARDBP-associated, sporadic and mutant SOD1-associated ALS. Results: We found altered expression of spliceosome components in motor neurons and widespread aberrations of mRNA splicing that specifically affected genes involved in ribonucleotide binding. This was confirmed in TDP-43 depleted NSC34 cells. Fibroblasts with mtTARDBP showed loss of nuclear TDP-43 protein and demonstrated similar changes in splicing and gene expression, that were not present in fibroblasts from patients with sporadic or SOD1-related ALS. Conclusion: Loss of nuclear TDP-43 is associated with RNA processing abnormalities in ALS motor neurons, patient-derived cells with mtTARDBP, and following artificial TDP-43 depletion, suggesting that splicing dysregulation directly contributes to disease pathogenesis. Key functional pathways affected include those central to RNA metabolism. RNA was extracted from lower motor neurons obtained by laser capture microdissection from autopsy material from neurologically healthy controls (n=6) and cases of sporadic ALS (n=3) and ALS due to C9ORF72 mutations (n=3).
2014-06-01 | E-GEOD-56500 | biostudies-arrayexpress
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:Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting loss of function may play a role in disease. We find that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS patient tissue. Thus, C9orf72 is required for normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.
2016-03-24 | GSE77681 | GEO