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HTA2.0 (human transcriptome array) analysis of control iPSC-derived motor neurons (MN), FUS-H517D-hetero-iPSC-MN, and FUS-H517D-homo-iPSC-MNs

ABSTRACT: To assess RNA regulation in the MN possessing mutated FUS-H517D gene. Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of familial amyotrophic lateral sclerosis (fALS). Mutated FUS causes accumulation of DNA damage stress and stress granule (SG) formation, etc., thereby motor neuron (MN) death. However, key molecular etiology of mutated FUS-dependent fALS (fALS-FUS) remains unclear. Here, Bayesian gene regulatory networks (GRN) calculated by Super-Computer with transcriptome data sets of induced pluripotent stem cell (iPSC)-derived MNs possessing mutated FUSH517D (FUSH517D MNs) and FUSWT identified TIMELESS, PRKDC and miR-125b-5p as "hub genes" which influence fALS-FUS GRNs. miR-125b-5p expression up-regulated in FUSH517D MNs, showed opposite correlations against FUS and TIMELESS mRNA levels as well as reported targets of miR-125b-5p. In addition, ectopic introduction of miR-125b-5p could suppress mRNA expression levels of FUS and TIMELESS in the cells. Furthermore, we found TIMELESS and PRKDC among key players of DNA damage stress response (DDR) were down-regulated in FUSH517D MNs and cellular model analysis validated DDR under impaired DNA-PK activity promoted cytosolic FUS mis-localization to SGs. Our GRNs based on iPSC models would reflect fALS-FUS molecular etiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118336 | GEO | 2021/04/19

REPOSITORIES: GEO

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RNA-seq analysis of NSC-34 mouse motor neuron-like cells treated with Negative Control siRNA#1 (siNC#1), siNC#2, Fus siRNA#1 (siFus#1), siFus#4, siFus#5 and siRNA (-) control

Project description:Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of familial amyotrophic lateral sclerosis (fALS). Mutated FUS causes accumulation of DNA damage and stress granule (SG) formation, etc., thereby motor neuron (MN) death. However, key molecular aetiology of mutated FUS-dependent fALS (fALS-FUS) remains unclear. Here, both regular bioinformatics and Bayesian gene regulatory networks (GRN) analyses were applied to large-scale transcriptome datasets of induced pluripotent stem cell (iPSC)-derived MNs possessing wild-type form of FUS and mutated FUSH517D (FUSH517D MNs). From regular bioinformatics provided DNA damage response (DDR)-related genes were uniformly down-regulated in FUSH517D MNs. Bayesian GRN calculated by Super-Computer identified miR-125b-5p, TIMELESS and PRKDC as "hub genes/miRNA" which influence the GRNs. miR-125b-5p was up-regulated in FUSH517D MNs and negatively correlated with FUS, TIMELESS and miR-125b-5p target mRNAs. Introduction of miR-125b-5p suppressed Fus, Timeless and DDR-related genes in addition to miR-125b-5p targets in expression, and caused DNA damage. Furthermore, knocking-down Timeless expression caused DNA damage. PRKDC was down-regulated in FUSH517D MNs and the cellular model analyses validated DNA damage under impaired DNA-PK activity promoted FUS mis-localization to SGs. Collectively, our strategy with Bayesian GRNs based on the iPSC model would provide the first compelling evidence to elucidate fALS-FUSH517D molecular aetiology.

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HTA2.0 (human transcriptome array) analysis of control iPSC-derived motor neurons (MN), FUS-H517D-hetero-iPSC-MN, and FUS-H517D-homo-iPSC-MNs

Project description:HTA2.0 (human transcriptome array) analysis of control iPSC-derived motor neurons (MN), FUS-H517D-hetero-iPSC-MN, and FUS-H517D-homo-iPSC-MNs

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Project description:We established several iPSCs from healthy donors, familial ALS (FALS) patients, and sporadic ALS (SALS) patients. Using our differentiation protocol originally developed, we differentiated these iPSCs toward spinal motor neurons (MNs) and reproduced ALS pathology in a dish. In addition, we screened a drug candidate which suppressed the detected ALS-related phenotypes of these ALS models. For clarifying the molecular mechanisms of the ALS pathologies and the screened drug, we used microarrays to detail the global program of gene expression reflecting the MN pathology of FALS/SALS, and carefully compared with healthy donors and/or drug-treated ALS models based on their expression profiles.

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Exon array analysis of control vs. FALS MPC

Project description:To assess RNA regulation in FALS for gene expression and alternative processing of RNA in the motor neuron precurssors (MPCs) Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disorder. Although its neuropathology is well understood, the cellular and molecular mechanisms that lead to the initiation and progression of this disease are yet to be elucidated due to limitations in the currently available human genetic data. In this study, we generated induced pluripotent stem cells (iPSC) from two familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation, and the isogenic iPSCs with the homozygous FUS H517D mutation obtained by genome editing from the healthy control iPSCs. These cell-derived motor neurons mimicked several neurodegenerative phenotypes. A part of the mutant FUS protein was localized outside the nucleus and co-localized with stress granules under stress conditions. Moreover, FALS motor neurons showed more apoptotic activity than did control motor neurons. Exon array analysis using motor neuron precursor cells (MPCs) combined with CLIP-seq data sets revealed aberrant gene expression and/or splicing pattern in FALS-MPCs. These results suggest that iPSC-derived motor neurons are a useful tool for analyzing the pathogenesis of human motor neuron disorders.

2016-02-01 | GSE76698 | GEO

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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.

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Project description:Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUSR521H mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in ALS6 MNs. Furthermore, ALS6 MNs are more sensitive to oxidative stress and display reduced expression of TGF-β and mTORC gene pathways when stressed. Finally, we show that IFNγ treatment reduces apoptosis of ALS6 MNs exposed to oxidative stress and partially restores the translation rates in ALS6 MNs. Overall, these findings suggest that a functional IFNγ response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.

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