Ontology highlight
ABSTRACT:
PROVIDER: PRJNA722770 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14268600_1.fastq.gz | Fastqsanger.gz | |||
| SRR14268600_2.fastq.gz | Fastqsanger.gz | |||
| SRR14268700_1.fastq.gz | Fastqsanger.gz | |||
| SRR14268700_2.fastq.gz | Fastqsanger.gz | |||
| SRR14268800_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: The FUS P525L mutation is highly penetrant and causes ALS cases with earlier disease onset and more aggressive progression. This study aims to understand the impact of P525L mutations in microglia during ALS pathogenesis. We compare the transcriptome (RNA-seq) of P525L mutations to the wildtype and isogenic controls to derive the differentially perturbed genes. Methods: Transcriptome profiles of human iPSC-derived microglia with gentoype of wild-type (WT), isogenic control (eCtrl), P525L homozygous (P525LHom), P525L heterozygous (P252LHet) and null deletion (KO) were generated using Illumina HiSeq2000 by multiplexed paired-read run with 100 cycles. Pass-QC sequencing reads were mapped to the human genome (hg19) using the OmicSoft ArrayStudio software followed by differential gene expression analysis via DESeq2 package. Results: Homozygous P525L mutations perturb the transcriptome profile where many differentially expressed genes are associated with microglial functions. Specifically, dysregulation of several chemoreceptor genes leads to altered chemoreceptor-activated calcium signaling. Conclusions: Our study underscores the cell- autonomous effects of the ALS-linked FUS P525L mutation in a human microglia model.
2022-02-03 | GSE172459 | GEO
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:Mutations in the RNA-binding protein FUS cause aggressive, early-onset forms of amyotrophic lateral sclerosis (ALS), leading to the progressive degeneration of the neuromuscular system. These mutations drive nuclear depletion and cytoplasmic mislocalisation of FUS, resulting in both loss and gain of function. We investigated these mechanisms and their impact on key pathophysiological processes in vivo, using a novel FUS-ALS mouse model. Adult mice presented widespread transcriptomic alterations consistent with nuclear loss of function, while translatome analysis revealed specific deficits associated with aberrant FUS-dependent cytoplasmic partitioning and gain of function. Mutant FUS expression selectively impaired neuromuscular junction (NMJ) innervation in FUS-ALS females. However, NMJ reinnervation following sciatic nerve crush was equally perturbed in homozygous mutants of both sexes, indicating impaired regeneration and damage responses. Additionally, we observed cargo-specific alterations in axonal transport, a process critical for neuronal function and maintenance; in vivo mitochondrial transport was impaired in homozygous FUS-ALS mice, whereas the retrograde transport of signalling endosomes was again only affected in mutant females, strengthening the link between endosomal transport impairment and NMJ denervation in ALS. Altogether, our findings establish FUS-ALS homozygous mice as a valuable model for investigating early cellular impairments driving ALS pathology, and identify broader and sex-dependent motor neuron dysfunction in FUS-ALS pathogenesis.
2025-05-29 | GSE298457 | GEO
Project description:Mutations in the RNA-binding protein FUS cause aggressive, early-onset forms of amyotrophic lateral sclerosis (ALS), leading to the progressive degeneration of the neuromuscular system. These mutations drive nuclear depletion and cytoplasmic mislocalisation of FUS, resulting in both loss and gain of function. We investigated these mechanisms and their impact on key pathophysiological processes in vivo, using a novel FUS-ALS mouse model. Adult mice presented widespread transcriptomic alterations consistent with nuclear loss of function, while translatome analysis revealed specific deficits associated with aberrant FUS-dependent cytoplasmic partitioning and gain of function. Mutant FUS expression selectively impaired neuromuscular junction (NMJ) innervation in FUS-ALS females. However, NMJ reinnervation following sciatic nerve crush was equally perturbed in homozygous mutants of both sexes, indicating impaired regeneration and damage responses. Additionally, we observed cargo-specific alterations in axonal transport, a process critical for neuronal function and maintenance; in vivo mitochondrial transport was impaired in homozygous FUS-ALS mice, whereas the retrograde transport of signalling endosomes was again only affected in mutant females, strengthening the link between endosomal transport impairment and NMJ denervation in ALS. Altogether, our findings establish FUS-ALS homozygous mice as a valuable model for investigating early cellular impairments driving ALS pathology, and identify broader and sex-dependent motor neuron dysfunction in FUS-ALS pathogenesis.
2025-05-29 | GSE298456 | GEO
Project description:Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that can be inherited with genetic mutations in > 25 different genes including e.g. FUS, TARDBP, and C9ORF72. It is currently unclear how these mutations lead to motor neuron degeneration and whether different gene mutations converge on similar pathogenic pathways early on, or if each mutation leads to motor neuron death in a unique manner. To address these questions in depth, we generated a number of isogenic iPSC (induced pluripotent stem cell) lines harbouring point mutations in FUS (R495X and P525L) or TARDBP (M337V) as well as a knock-out of FUS (FUS-KO), to discern loss-versus gain-of-function mechanisms in FUS. The use of isogenic lines enables identification of subtle early disturbances in the transcriptome which may be detrimental but impossible to detect when lines of different backgrounds are used. We conducted single cell RNA sequencing of motor neurons and interneurons derived from these lines using Smart-seq2. We show that ALS-causative mutations elicit a much larger transcriptional response in motor neurons than in interneurons. A large number of transcripts were coregulated across FUS R495X and P525L motor neurons and the majority of these were part of gain-of-function of FUS. Cross-comparison with isogenic ALS-linked TARDBP M337V identified an early dysfunctions shared across ALS-causative mutations unique to motor neurons that could have major implications for motor neuron survival and that might be targeted therapeutically.
2025-04-30 | GSE226482 | GEO
Project description:Mutations in Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo. We demonstrate that depletion of Drosha mitigates FUS-mediated degeneration, survival, and motor defects in Drosophila. Mutant FUS strongly interacts with Drosha and causes its cytoplasmic mis-localization into the insoluble FUS inclusions. Reduction in Drosha levels increases the solubility of mutant FUS. Interestingly, we found two Drosha dependent microRNAs, miR-378i and miR-6832-5p, which differentially regulate the expression, solubility, and cytoplasmic aggregation of mutant FUS in iPSC neurons and mammalian cells. More importantly, we report different modes of action of these miRNAs against mutant FUS. Whereas miR-378i may regulate mutant FUS inclusions by preventing G3BP-mediated stress granule formation, miR-6832-5p may affect FUS expression via other proteins or pathways. Overall, our research reveals a possible association between ALS-linked FUS mutations and the Drosha-dependent miRNA regulatory circuit, as well as a useful perspective on potential ALS treatment via microRNAs.
2023-09-09 | GSE242360 | GEO
Project description:Mutations in coding and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS). The latter mutations may exert toxicity by increasing FUS accumulation. We showhere that broad expression within the nervous system of wild type or either of two ALS-linkedmutants of human FUS produces progressive motor phenotypes accompanied bycharacteristic ALS-like pathology. FUS levels are autoregulated by a mechanism in whichwild type or ALS-linked mutants of human FUS downregulating endogenous FUS at bothmRNA and protein levels. Increasing wild type human FUS expression achieved bysaturating this autoregulatory mechanism produces a rapidly progressive neurologicalphenotype and dose-dependent lethality. Genome-wide expression analysis reveals mis-regulation of genes that are largely distinct from the alterations observed by the acute FUS reduction in the spinal cord. Among these are increased expression of lysosomal proteins,suggestive of disruption in protein homeostasis as a potential gain-of-toxic mechanism.Indeed, increased expression of wild type and ALS-linked mutations in FUS inhibitautophagy with accumulated p62/sequestosome observed in spinal cord motor neurons.Taken together, our data suggests that overriding FUS autoregulation triggers gain-of-toxicproperties in the autophagy-lysosome axis and deregulation of RNA metabolism, highlightinga disruption in protein and RNA homeostasis in FUS-mediated toxicity.
2019-01-16 | GSE125125 | GEO
Project description:The RNA-binding protein FUS/TLS, mutation in which is causative of the fatal motor neuron disease ALS, is demonstrated to directly bind to the U1-snRNP and SMN complexes. ALS-causative mutations in FUS/TLS are shown to abnormally enhance their interaction with SMN and reduce interaction with U1-snRNP. Correspondingly, global RNA analysis reveals a mutant-dependent loss of splicing activity, with ALS-linked mutants failing to reverse changes caused by loss of wild-type FUS/TLS. Furthermore, a common FUS/TLS mutant-associated RNA splicing signature is identified in ALS patient fibroblasts. Taken together, our studies establish potentially converging disease mechanisms in ALS and spinal muscular atrophy, with ALS-causative mutants acquiring properties representing both gain (dysregulation of SMN) and loss (reduced RNA processing mediated by U1-snRNP) of function. RNA-mediated oligonucleotide Annealing, Selection, and Ligation with Next-Generation sequencing (RASL-seq) method was used for analyzing alternative splicing changes. Oligonucleotide probes are designed to anneal to the exon-exon junctions. The probe library was assembled to assess 5530 unique alternative splicing events, most of which were exon inclusion or skipping, with a minority for alternative 5’- or 3’- splice sites. The splicing changes were compared among groups of reducing FUS/TLS or SMN levels, or expressing various FUS mutations to determine the loss versus gain of FUS/TLS function on splicing regulation.
2015-02-10 | E-GEOD-64078 | biostudies-arrayexpress
Project description:Mutations in the RNA binding protein, Fused in Sarcoma (FUS), lead to amyotrophic lateral sclerosis (ALS), the most frequent form of motor neuron disease. Cytoplasmic aggregation and defective DNA repair machinery are etiologically linked to mutant FUS-associated ALS. Although FUS is involved in numerous aspects of RNA processing, little is understood about the pathophysiological mechanisms of mutant FUS. Here, we employed RNA-sequencing technology in Drosophila brains expressing FUS to identify significantly altered genes and pathways involved in FUS-mediated neurodegeneration.
2021-05-05 | GSE173838 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE40649: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (microarray) GSE40651: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (CLIP-Seq) GSE40652: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (RNA-Seq) Refer to individual Series
2012-09-30 | E-GEOD-40653 | biostudies-arrayexpress