Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJDB11489 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR286996.fastq.gz | Fastqsanger.gz | |||
| DRR286997.fastq.gz | Fastqsanger.gz | |||
| DRR286998.fastq.gz | Fastqsanger.gz | |||
| DRR286999.fastq.gz | Fastqsanger.gz | |||
| DRR287000.fastq.gz | Fastqsanger.gz |
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Project description:We produce RNA-seq datasets of iPSC-derived motor neurons (iPSC-MN) from healthy controls and sporadic ALS patients and controls and familial ALS patients with pathogenic variants in TARDBP.
| EGAS00001005879 | EGA
Project description:Amyotrophic Lateral Sclerosis is a fatal neurodegenerative disorder that affects motor neurons (MN). We used single cell RNA-seq of degenerating human MN derived from ALS patients to understand molecular drivers of MN degeneration. Patient-derived iPSC bearing a point mutation in the SOD1 gene (SOD1 E100G) were differentiated into MN. MN derived from CRISPR-Cas9 corrected isogenic control iPSC (SOD1 E100E) were used as control. Survival analysis indicated that at 44 days of in vitro differentiation, ALS MN dislpayed survival deficits. At this point, cells were harvested for single cell transcriptomics using the Fluidigm C1 system.
2019-11-01 | E-MTAB-7353 | biostudies-arrayexpress
Project description:Sequencing of human iPS-derived motor neurons from fibroblasts of Amyotrophic lateral sclerosis patients with an M337V mutation in TARDBP and comparison with age matched healthy controls identify differences in glutamate receptor and mitochondrial calcium buffering channels.
2020-03-26 | GSE147544 | GEO
Project description:We established iPSCs from healthy donors, SOD1-ALS and TDP43-ALS patients. Using our differentiation protocol originally developed by Reinhardt et al.,2013, we diferentiated these iPSCs toward spinal motor neurons (MNs) and reproduce ALS pathology in a dish. To extend our understanding of finding different molecular mechanisms and pathways related to SOD1- and TDP43 mutations in ALS disease, we have performed a comprehensive gene expression profiling study using RNA-Seq of the iPSC-derived MN models from control individuals and carefully compared with those from SOD1-ALS and TDP43-ALS patients. To generate novel hypotheses of putative underlying molecular mechanisms in ALS, we used human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs) from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to perform high-throughput RNA-sequencing (RNA-Seq). An integrated bioinformatics approach was employed to identify differentially expressed genes (DEGs) and key pathways underlying these familial forms of the disease (fALS). In TDP43-ALS, we found dysregulation of transcripts encoding components of the transcriptional machinery and transcripts involved in splicing regulation were particularly affected. In contrast, less is known about the role of SOD1 in RNA metabolism in motor neurons. Here we found that many transcripts relevant for mitochondrial function were specifically altered in SOD1-ALS, indicating transcriptional signatures and expression patterns can vary significantly depending on the causal gene that is mutated. Surprisingly, however, we identified a clear downregulation of genes involved in protein translation in SOD1-ALS suggesting that ALS-causing SOD1 mutations shift cellular RNA abundance profiles to cause neural dysfunction. Altogether, we provided here an extensive profiling of mRNA expression in two ALS models at the cellular level, corroborating the major role of RNA metabolism and protein translation as a common pathomechanism in ALS
2022-08-17 | GSE210969 | 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 fibroblasts grown from neurologically healthy controls (n=6) and 3 groups of patients with ALS: 1) sporadic cases (n=6); 2) cases due to mutations of SOD1 (n=4); 3) cases due to mutations of TARDBP (n=3). The three ALS groups were compared to the controls.
2014-06-01 | E-GEOD-33855 | biostudies-arrayexpress
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:Although the pathological hallmark of amyotrophic lateral sclerosis (ALS) is the nucleocytoplasmic mislocalisation of RNA binding proteins (RBPs), such as TDP-43 and FUS, the nucleocytoplasmic distribution of mRNA remains uncharacterised. Here, we used subcellular fractionation with RNA sequencing and proteomics to assess nucleocytoplasmic mRNA and protein localisation in human induced pluripotent stem cell-derived motor neurons (iPSNs) from ALS patients with TARDBP mutations, VCP mutations, and controls with VCP mutations knocked-in with CRISPR/Cas9. In each mutant group, we found substantial nucleocytoplasmic mRNA redistribution, particularly in transcripts involved in protein binding. Redistributed transcripts in ALS iPSNs were enriched in protein-coding biotypes, exhibited longer lengths, and had enhanced interactions with RBPs, including TDP-43 and FUS. Using mass spectrometry in TARDBP mutant, VCP mutant, and VCP mutant knock-in iPSNs, we reveal widespread protein mislocalisation, especially in RBPs. We find that mislocalised proteins exhibit substantially greater binding to redistributed transcripts than non-redistributed mRNAs, suggesting that RBP mislocalisation may be directly coupled to mRNA redistribution. Remarkably, treatment with the VCP D2 ATPase domain inhibitor ML240 restored both nucleocytoplasmic mRNA redistribution and protein mislocalisation not only in VCP mutants but also in TARDBP mutant iPSNs. Functional assays in VCP mutant iPSNs further confirmed that ML240 restores lysosomal localisation from the perinuclear region towards the neurites and reduces oxidative stress. Our findings demonstrate that ALS motor neurons exhibit concomitant nucleocytoplasmic mRNA redistribution and RBP
2023-10-13 | PXD037107 | Pride
Project description:Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of ALS patients, but the contribution of axonal TDP-43 to this fatal neurodegenerative disease is unclear. Here, we find TDP-43 accumulation in the axons of intra-muscular nerves from ALS patients, and in motor neurons and neuromuscular junctions(NMJs) of a mouse model with TDP-43 mislocalization. This leads to the formation of G3BP1- and TDP-43-positive RNA-granules in motor neuron axons, and to inhibition of local protein synthesis in axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondria proteins are reduced. Clearance of axonal TDP-43 restored local translation of the nuclear-encoded mitochondrial proteins and rescued TDP-43-derived axonal and NMJ toxicity. These findings suggest that targeting TDP-43 axonal gain of function may mediata therapeutic effect in ALS.
2021-11-04 | PXD021876 | Pride
Project description:We established iPSCs from healthy donors, FUS-ALS and SOD1-ALS patients. Using our differentiation protocol originally developed by Reinhardt et al.,2013, we diferentiated these iPSCs toward spinal motor neurons (MNs) and reproduce ALS pathology in a dish. To extend our understanding of finding different molecular mechanisms and pathways related to FUS- and SOD mutations in ALS disease, we have performed a comprehensive gene expression profiling study using microarray hybridization of the iPSC-derived MN models from control individuals and carefully compared with those from FUS-ALS and SOD1-ALS patients. In addition, we further analyzed previously published independent datasets containing the genome-wide RNA profiling of iPSC-derived MN samples from patients with FUS and SOD1 mutations and controls. This microaray dataset GSE10638 (Fujimori et al., 2018) was retrieved from GEO database and was screened to identifiy potential drug candidates which suppressed the detected ALS-related phenotypes of these ALS models. Finally, we made a systematic comparison with our results to the ones independently obtained previously.Here through this study, we create a gene profile of ALS by analyzing the differentially expressed genes (DEGs), the kyoto encyclopedia of Genes and Genomes (KEGG) pathways, the interactome as well as transcription factor profiles (TF) that would identify altered functional/molecular signatures and their interactions at both transcriptional (mRNAs) and translational levels (hub proteins and TFs) which stands validation across the different datasets (including different differentiation protocols etc.). By doing so we provide condensed pathophysiological pathways of FUS-ALS and SOD1-ALSto better understand the biological mechanisms underlying motor neuron disease.
2020-09-21 | GSE158264 | 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 NSC34 motor neuronal cells depleted of TDP-43 by shRNA (n=4), treated with control shGFP (n=4), and treated with control shLuciferase (n=3).
2014-06-01 | E-GEOD-56503 | biostudies-arrayexpress