FUS-NLS mutation causes neurodevelopmental and systemic metabolic alterations
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1028651 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26402939_1.fastq.gz | Fastqsanger.gz | |||
| SRR26402939_2.fastq.gz | Fastqsanger.gz | |||
| SRR26402940_1.fastq.gz | Fastqsanger.gz | |||
| SRR26402940_2.fastq.gz | Fastqsanger.gz | |||
| SRR26402941_1.fastq.gz | Fastqsanger.gz |
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Project description:Mutations in the ubiquitously expressed DNA/RNA binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). While most FUS mutation studies have focused on motor neuron degeneration, little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues given the link between ALS-FTD and altered metabolism.
2023-10-19 | GSE245520 | GEO
Project description:Variants in the ubiquitously expressed DNA/RNA-binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). Most FUS mutation studies have focused on motor neuron degeneration; little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues, given the link between ALS-frontotemporal dementia and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. Magnetic resonance imaging brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller than heterozygous and wild-type brains and displayed significant morphological alterations, including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. These findings show that the disease aetiology of FUS variants can include both neurodevelopmental and systemic alterations.
| S-EPMC10642611 | biostudies-literature
Project description:FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS. Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knock-in mice expressing mislocalized cytoplasmic FUS and complete FUS knock-out mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knock-in mice, but not FUS knock-out mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. Total RNA from brains of E18.5 knock-in (FusÎNLS/ÎNLS), and knock-out (Fus-/-) mice and their control littermates were extracted with Trizol and libraries were prepared for RNA sequencing and RNA-mediated oligonucleotide Annealing, Selection, and Ligation with Next-Generation sequencing (RASL-seq) (Li et al. 2012; Zhou et al. 2012). For the RNA-seq experiment, biological replicates were used with n=4-5 knock-in animals per group (4 wild-type and 5 homozygous FusÎNLS) and n=5 knock-out animals per group (5 wild-type and 5 homozygous Fus-/-). For the RASL-seq analysis, biological replicates were used with n=4 knock-in animals per group (4 wild-type, 4 heterozygous and 4 homozygous FusÎNLS) and n=5 animals per group (5 wild-type and 5 homozygous Fus-/- knock-out).
2016-03-14 | E-GEOD-78730 | biostudies-arrayexpress
Project description:Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease in which the loss of motor neurons induces progressive weakness and death from respiratory failure, typically only 3-5 years after onset. FUS has been established to have a role in numerous aspects of RNA processing, including splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterised, as most disease models have been based on FUS overexpression, which in itself alters its RNA processing functions. To overcome this, we and others have recently created knock-in models, and have generated high depth RNA-sequencing data on FUS mutants in parallel to FUS knockout
2020-03-21 | GSE147288 | GEO
Project description:FUS ALS seems to preferentially affect sMNs, and cognitive dysfunction in FUS ALS is rare. Considering this, we wanted to analyze if cortical neurons behave differently than spinal motor neurons in response to FUS mutations. For this, we used cortical neurons derived from isogenic human induced pluripotent stem cells (hiPSCs) in which either WT or NLS mutant FUS P525L was tagged with eGFP using CRISPR/Cas9 and systematically compared them to sMNs of the identical iPSCs. Phenotypically, mutant FUS cortical neurons showed less impairment of FUS recruitment to DNA damage sites compared to mutant sMNs and less signs of DNA damage, which were similarly found in post mortem tissue. To advance our understanding of finding different molecular mechanisms and pathways related to FUS mutations in ALS disease, we have performed RNA sequencing of FUS ALS cortical and spinal motor neurons and our results revealed basic differences in their transcriptomes. Alternative splicing events in spinal motor neurons were different from cortical neurons also pointing towards DNA damage in FUS ALS.
2024-08-27 | GSE272827 | GEO
Project description:FUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNA, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages. Despite apparently unaltered synaptic organization, RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS relocalization to the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration.
2021-03-05 | E-MTAB-9211 | biostudies-arrayexpress
Project description:FUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNA, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages. Despite apparently unaltered synaptic organization, RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS relocalization to the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration.
2021-03-05 | E-MTAB-9212 | biostudies-arrayexpress
Project description:The aim of our study is to identify the role of FUS in shaping the transcriptome. RNA-seq of two FUS KO clones was performed and compared to wt; for each, four replicates were sequenced. RNA molecules associated with the FUS protein were determined by means of a RNA immuno-precipitation, followed by high-throughput sequencing. Total RNA was used as a control. SH-SY5Y cells were used for both experiments. RNA-seq: 4 wt samples, 4 A4 KO samples, 4 A5 KO samples. RIP-seq: 1 input control sample, 3 anti-FUS IP replicates.
2016-06-13 | E-GEOD-71812 | biostudies-arrayexpress
Project description:FUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNA, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages. Despite apparently unaltered synaptic organization, RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS relocalization to the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration.
2021-03-05 | E-MTAB-10104 | biostudies-arrayexpress