E4e80b6b-f42f-4944-b55e-990b6a129d9f - samples
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ABSTRACT:
PROVIDER: EGAD00001008425 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:iPSC-derived motor neurons form sporadic ALS and Controls. 4 sALS iPSC lines and 4 Ctrl iPSC lines.
| EGAD00001008424 | EGA
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: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:Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are a strong genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we developed a human iPSC-derived model to investigate whether motor neurons derived from ALS patients carrying ATXN2 intermediate repeat expansions are transcriptomically distinct from healthy controls. For that, we performed RNA sequencing of motor neurons derived from 5 ATXN2-ALS iPSC lines and 5 healthy controls (HC).
2024-07-16 | GSE224578 | GEO
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:TDP-43 is the major component of pathological inclusions in most ALS patients and in up to 50% of patients with frontotemporal dementia (FTD). Heterozygous missense mutations in TARDBP, the gene encoding TDP-43, are one of the common causes of familial ALS. In this study, we investigate TDP-43 protein behavior in induced pluripotent stem cell (iPSC)-derived motor neurons from three ALS patients with different TARDBP mutations and three healthy controls. TARDPB mutations induce several TDP-43 changes in spinal motor neurons, including cytoplasmic mislocalization and accumulation of insoluble TDP-43, C-terminal fragments and phospho-TDP-43. By generating iPSC lines with allele-specific tagging of TDP-43, we find that mutant TDP-43 initiates the observed disease phenotypes and has an altered interactome as indicated by mass spectrometry-based proteomics. Our findings also indicate that TDP-43 proteinopathy results in a defect in mitochondrial transport. Lastly, proteomics analyses also show that pharmacological inhibition of histone deacetylase 6 (HDAC6) restores the observed TDP-43 pathologies and the axonal mitochondrial motility, suggesting that HDAC6 inhibition may be an interesting therapeutic target for neurodegenerative disorders linked to TDP-43 pathology.
2021-03-15 | PXD023852 | Pride
Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear TDP-43. Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-mRNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from sporadic ALS patients and familial ALS patients with expansion in C9orf72, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity. Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS/FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.
2019-01-01 | GSE122069 | GEO
Project description:Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder with complex origins. Familial monogenetic causes of ALS make up a small percentage of patients overall, and the cause of the majority of idiopathic (sporadic) form remains unknown. Frequently utilized for disease modeling, human induced pluripotent stem cell (iPSC)-derived motor neuron cultures lack cellular maturity in vitro and rarely recapitulate clinically relevant phenotypes of ALS. Microfluidic organ-on-chip systems enable co-culture of multiple disease-relevant cell types and enhance cellular maturity. Here, we describe the generation of spinal cord (SC)-chips from 8 sporadic ALS (sALS) patients and 10 non-diseased controls. Transcriptomic and proteomic analyses of SC-Chips revealed changes in expression of targets known to be disrupted in ALS patients. Particularly, intermediate filaments (IF) neurofilament heavy (NEFH), medium (NEFM), and light (NEFL) were upregulated in SC-Chips from sALS patients. Single nuclei RNAseq (sNucseq) of SC-Chips revealed two subpopulations of motor neurons and cell-specific changes related to ALS pathogenesis and mimicking conditions in vivo.
2025-06-24 | GSE255605 | GEO
Project description:Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder with complex origins. Familial monogenetic causes of ALS make up a small percentage of patients overall, and the cause of the majority of idiopathic (sporadic) form remains unknown. Frequently utilized for disease modeling, human induced pluripotent stem cell (iPSC)-derived motor neuron cultures lack cellular maturity in vitro and rarely recapitulate clinically relevant phenotypes of ALS. Microfluidic organ-on-chip systems enable co-culture of multiple disease-relevant cell types and enhance cellular maturity. Here, we describe the generation of spinal cord (SC)-chips from 8 sporadic ALS (sALS) patients and 10 non-diseased controls. Transcriptomic and proteomic analyses of SC-Chips revealed changes in expression of targets known to be disrupted in ALS patients. Particularly, intermediate filaments (IF) neurofilament heavy (NEFH), medium (NEFM), and light (NEFL) were upregulated in SC-Chips from sALS patients. Single nuclei RNAseq (sNucseq) of SC-Chips revealed two subpopulations of motor neurons and cell-specific changes related to ALS pathogenesis and mimicking conditions in vivo.
2025-06-24 | GSE255602 | GEO
Project description:RNA sequencing analysis of human iPSC-derived motor neurons generated from two C9ORF72 ALS/FTD patient lines, treated with negative control ASO (NC ASO) or PIKFYVE ASO. The goal of this study is to evaluate the effect of PIKFYVE suppression in rescuing ALS motor neuron degeneration.
2022-12-18 | GSE221016 | GEO