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Transcriptome-wide identification of nuclear and cytoplasmic RNA-binding sites of FUS RBD-only constructs

ABSTRACT: We report the binding sites of three FUS constructs: (1) The full-length protein (FL); (2) A deletion mutant consisting of amino acids 242-526 (CT); and (3) A aa 242-526 deletion mutant with ALS-associated P525L mutation and heterologous nuclear export signal (CTstar) with the aim to assess the role of protein-protein interactions on RNA-binding and to identify nuclear and cytoplasmic RNA-binding sites of Fused in Sarcoma (FUS).

ORGANISM(S): Homo sapiens

PROVIDER: GSE139263 | GEO | 2020/10/21

REPOSITORIES: GEO

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RNA-seq to investigate the phase separation-dependent FUS RNA interactome

Project description:The protein Fused in Sarcoma undergoes liquid-liquid phase separation. To investigate whether this phase transition alters the RNA interactome we purified phase-separated FUS droplets and soluble FUS from HEK 293T cells transfected with GFP-tagged WT FUS or P525L FUS. Phase separated FUS was purified by fluorescence-activated particle sorting (droplets) and soluble FUS by co-Immunoprecipitation (IP) respectively followed by isolation of co-purified RNA. Here we show that phase separation affects the RNA interactome of FUS.

2021-06-23 | E-MTAB-8456 | biostudies-arrayexpress

A study of how homozygous ALS-linked FUS P525L mutations perturb transcriptome profile in human iPSC-derived microglia

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

Transcriptome-wide identification of nuclear and cytoplasmic RNA-binding sites of FUS RBD-only constructs

Project description:Transcriptome-wide identification of nuclear and cytoplasmic RNA-binding sites of FUS RBD-only constructs

| PRJNA578929 | ENA

Mutant FUS and ELAVL4 (HuD) aberrant crosstalk in Amyotrophic Lateral Sclerosis

Project description:Determination of RNAs bound by wildtype and P525L mutant FUS in human iPSC-derived motoneurons using PAR-CLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation)

2019-06-13 | GSE118347 | GEO

FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy

Project description:Unraveling the mechanistic link connecting the multiple RNA-binding proteins (RBPs) associated with amyotrophic lateral sclerosis (ALS) is critical for identifying novel therapeutics. Mutations in the RBP FUS cause the third most common genetic form of ALS. Here, we show that motor neurons (MNs) of FUS-ALS patients manifest heterogeneous levels of cytoplasmic FUS. Using neurons differentiated from induced pluripotent stem cells (iPSCs) carrying a FUS-eGFP reporter, we demonstrate that pronounced cytoplasmic FUS mislocalization is linked to aberrant protein degradation. We also show that the P525L FUS mutation reduces the interaction of FUS with RBPs, including hnRNPA1, hnRNPA2B1, EWSR1, and TAF15, facilitating FUS aggregation. Additionally, RBP levels are decreased, inducing neurodegeneration. We use patient spinal cord to demonstrate that MNs containing aggregated FUS have reduced RBP content compared to MNs lacking FUS aggregates. Finally, we demonstrate that small molecules inducing autophagy, including PQR309, a brain penetrant compound in clinical trials, restore proteostasis.

2019-03-26 | PXD010966 | Pride

Mutant FUS triggers age-dependent synaptic impairment in presymptomatic ALS-FUS mice (RNA-seq part2)

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

Mutant FUS triggers age-dependent synaptic impairment in presymptomatic ALS-FUS mice (CLIP-seq)

2021-03-05 | E-MTAB-9211 | biostudies-arrayexpress

Mutant FUS triggers age-dependent synaptic impairment in presymptomatic ALS-FUS mice (RNA-seq)

2021-03-05 | E-MTAB-9212 | biostudies-arrayexpress

Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss

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.

2016-03-14 | GSE78730 | GEO

Activation of polo-like kinase 1 expression in spinal motor neurons as vulnerability factor of spinal motor neurons in FUS- and other fALS

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

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