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

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE118347 | GEO | 2019/06/13

REPOSITORIES: GEO

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Mutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis.

Project description:Amyotrophic lateral sclerosis (ALS) has been genetically linked to mutations in RNA-binding proteins (RBPs), including FUS. Here, we report the RNA interactome of wild-type and mutant FUS in human motor neurons (MNs). This analysis identified a number of RNA targets. Whereas the wild-type protein preferentially binds introns, the ALS mutation causes a shift toward 3' UTRs. Neural ELAV-like RBPs are among mutant FUS targets. As a result, ELAVL4 protein levels are increased in mutant MNs. ELAVL4 and mutant FUS interact and co-localize in cytoplasmic speckles with altered biomechanical properties. Upon oxidative stress, ELAVL4 and mutant FUS are engaged in stress granules. In the spinal cord of FUS ALS patients, ELAVL4 represents a neural-specific component of FUS-positive cytoplasmic aggregates, whereas in sporadic patients it co-localizes with phosphorylated TDP-43-positive inclusions. We propose that pathological mutations in FUS trigger an aberrant crosstalk with ELAVL4 with implications for ALS.

| S-EPMC6613039 | biostudies-literature

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

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

| PRJNA485313 | ENA

Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity

Project description:We employ CLIP-Seq, RNA-Seq and Ribo-Seq in cultured neurons expressing R495X or wild-type FUS to identify effects of the mutation on the FUS targetome and on the neuronal transcriptome at the expression and translation level

2017-11-01 | GSE106386 | GEO

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

MiR-129-5p downregulates HuD expression impairing neuritogenesis in Amyotrophic Lateral Sclerosis

Project description:Amyotrophic lateral sclerosis (ALS) involves the degeneration of brain and spinal cord motor neurons. Mutations in Superoxide Dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43) and Fused-in-Sarcoma (FUS) account for 20-30 % of the familial ALS (fALS) cases. The RNA-binding proteins TDP-43 and FUS function in mRNA and miRNA biogenesis. MiRNAs are required for survival of neurons and deregulation of miRNA expression has been reported in several neurodegenerative disorders. Here, we report the dysregulation of DROSHA, DGCR8, and DICER in human neuroblastoma SH-SY5Y cells expressing the ALS-associated SOD1(G93A) mutant protein. MiRNA profiling in SH-SY5Y/SOD1(G93A) cells and transgenic SOD1(G93A) mice revealed upregulation of miR-129-5p at the early stage of disease. Moreover, miR-129-5p is also upregulated in lymphocytes of sporadic ALS patients. We demonstrate that miR-129-5p targets ELAVL4/HuD mRNA by binding to its 3’ UTR, which reduces HuD expression and impairs differentiation and neurite outgrowth. Conversely, treatment with an antagomir or complementation with HuD protein restores neuritogenesis. Collectively, our study identifies miR-129-5p and HuD as key regulators of neuronal differentiation and as potential therapeutic targets for ALS.

2018-02-01 | GSE94379 | GEO

Multiomics approach reveal novel insights in FUS driven Juvenile Amyotrophic Lateral Sclerosis: a family quartet analysis

Project description:We have identified a novel de novo variation in FUS gene in a sporadic juvenile ALS patient. FUS is an RNA-binding protein actively involved in various aspect of nucleic acid metabolism. We performed RNA-seq to identify altered transcriptome in juvenile ALS.

2024-05-25 | GSE232929 | GEO

Project description:Mutations in the RNA-binding protein (RBP) FUS have been genetically associated with the motoneuron disease amyotrophic lateral sclerosis (ALS). Using both human induced pluripotent stem cells and mouse models, we found that FUS-ALS causative mutations affect the activity of two relevant RBPs with important roles in neuronal RNA metabolism: HuD/ELAVL4 and FMRP. Mechanistically, mutant FUS leads to upregulation of HuD protein levels through competition with FMRP for HuD mRNA 3'UTR binding. In turn, increased HuD levels overly stabilize the transcript levels of its targets, NRN1 and GAP43. As a consequence, mutant FUS motoneurons show increased axon branching and growth upon injury, which could be rescued by dampening NRN1 levels. Since similar phenotypes have been previously described in SOD1 and TDP-43 mutant models, increased axonal growth and branching might represent broad early events in the pathogenesis of ALS.

| S-EPMC8410767 | biostudies-literature

The FUS protein participates in circRNA biogenesis

Project description:The RNA binding protein FUS exerts its function in several RNA biosynthetic processes; moreover, mutations leading to changes in its expression levels or alterations in cellular compartmentalization have been linked to the pathogenesis of Amyotrophic Lateral Sclerosis. Here, we describe an additional novel function of FUS, that is the control of back-splicing reactions which lead to circular RNA (circRNA) production. We identified circRNAs expressed in murine ES-derived motoneurons and then compared their levels in control versus FUS-/- cells. We discovered that a considerable number of circRNAs is affected by FUS levels.

2017-02-27 | GSE83226 | GEO

HuD (ELAVL4) gain-of-function impairs neuromuscular junctions and induces apoptosis in in vitro and in vivo models of amyotrophic lateral sclerosis.

Project description:Early defects at the neuromuscular junction (NMJ) are among the first hallmarks of the progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS). According to the "dying back" hypothesis, disruption of the NMJ not only precedes, but is also a trigger for the subsequent degeneration of the motoneuron in both sporadic and familial ALS, including ALS caused by the severe FUS pathogenic variant P525L. However, the mechanisms linking genetic and environmental factors to NMJ defects remain elusive. By taking advantage of co-cultures of motoneurons and skeletal muscle derived from human induced pluripotent stem cells (iPSCs), we show that the neural RNA binding protein HuD (ELAVL4) may underlie NMJ defects and apoptosis in FUS-ALS. HuD overexpression in motoneurons phenocopies the severe FUSP525L mutation, while HuD knockdown in FUSP525L co-cultures produces phenotypic rescue. We validated these findings in vivo in a Drosophila FUS-ALS model. Neuronal-restricted overexpression of the HuD-related gene, elav, produces per se a motor phenotype, while neuronal-restricted elav knockdown significantly rescues motor dysfunction caused by FUS. Finally, we show that HuD levels increase upon oxidative stress in human motoneurons and in sporadic ALS patients with an oxidative stress signature. On these bases, we propose HuD as an important player downstream of FUS mutation in familial ALS, with potential implications for sporadic ALS related to oxidative stress.

| S-EPMC10925158 | biostudies-literature

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