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The protective effect of edaravone on TDP-43 plus oxidative stress-induced neurotoxicity in neuronal cells: Analysis of its neuroprotective mechanisms using RNA sequencing

ABSTRACT: The protective effect of edaravone on TDP-43 plus oxidative stress-induced neurotoxicity in neuronal cells: Analysis of its neuroprotective mechanisms using RNA sequencing

PROVIDER: PRJNA856268 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20001173_1.fastq.gz	Fastqsanger.gz
	SRR20001173_2.fastq.gz	Fastqsanger.gz
	SRR20001174_1.fastq.gz	Fastqsanger.gz
	SRR20001174_2.fastq.gz	Fastqsanger.gz
	SRR20001175_1.fastq.gz	Fastqsanger.gz

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The protective effect of edaravone on TDP-43 plus oxidative stress-induced neurotoxicity in neuronal cells: Analysis of its neuroprotective mechanisms using RNA sequencing

Project description:Edaravone is a free-radical scavenger drug that was recently approved for the treatment of amyo-trophic lateral sclerosis (ALS), a neurodegenerative disease. A pathological hallmark of ALS is the accumulation of ubiquitinated or phosphorylated aggregates of the 43-kDa transactive response DNA binding protein (TDP-43) within the cytoplasm of motor neurons. This study revealed the efficacy of edaravone in preventing neuronal cell death in a TDP-43 proteinopathy model and analyzed the molecular changes associated with the neuroprotection. The viability of the neuronal cells expressing TDP-43 was reduced by oxidative stress, and edaravone (≥10 μmol/L) protected in a concentration-dependent manner against the neurotoxic insult. Differential gene expression analysis revealed changes among pathways related to nuclear erythroid 2-related-factor (Nrf2)-mediated oxidative stress response in cells expressing TDP-43. In edaravone-treated cells express-ing TDP-43, significant changes in gene expression were also identified among Nrf2-oxidative re-sponse, unfolded protein response, and autophagy pathways. In addition, the expression of genes belonging to phosphatidylinositol metabolism pathways was modified. These findings suggest that the neuroprotective effect of edaravone involves the prevention of TDP-43 misfolding and en-hanced clearance of pathological TDP-43 in TDP-43 proteinopathy.

2022-07-11 | GSE207578 | GEO

TDP-43 Neurotoxicity in late D. melanogaster pupae

Project description:The aim of this study is to understand the mechanisms of TDP-43 neurotoxicity. Here, we perform a RNA-Seq analysis in TDP-43 gain-of-fucntion (GOF) , TDP-43 loss-of-function and wild-type late pupae heads (73-90 hours APF) and perform TDP-43 GOF vs wild type and TDP-43 LOF vs wild-type differential expression analysis to show that both mechanisms presents defects in ecdysone receptor (ECR)-dependeint transcriptional program switching, and strongly deregulate expression from the neuronal microtubule associated protien Map205. RNA-seq was performed in two wild-type D.melanogaster biological replicates (Canton S, w1118 ), four biological replicates for TDP-43 (LOF) with two distinct genotypes (dTDP-43Δ142/Df(2R)106,dTDP-43Δ23/Δ142 ) and two TDP-43 GOF biological replicates (act5c>dTDP-43 ).

2013-01-22 | E-GEOD-42844 | biostudies-arrayexpress

TDP-43 Neurotoxicity in late D. melanogaster pupae

2013-01-22 | GSE42844 | GEO

U373MG edaravone and carnosic acid

Project description:We investigated the gene expression profiles of U373MG human astrocytoma cells treated with vehicle (DMSO) or edaravone or carnosic acid) or both edaravone and carnosic acid. Edaravone is a free radical scavenger sold as radicut. Carnosic acid is a phytochemical found in rosemary and sage.

2019-04-30 | GSE129001 | GEO

The Protective Effect of Edaravone on TDP-43 Plus Oxidative Stress-Induced Neurotoxicity in Neuronal Cells: Analysis of Its Neuroprotective Mechanisms Using RNA Sequencing.

Project description:Edaravone is a free-radical scavenger drug that was recently approved for the treatment of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. A pathological hallmark of ALS is the accumulation of ubiquitinated or phosphorylated aggregates of the 43-kDa transactive response DNA binding protein (TDP-43) within the cytoplasm of motor neurons. This study revealed the efficacy of edaravone in preventing neuronal cell death in a TDP-43 proteinopathy model and analyzed the molecular changes associated with the neuroprotection. The viability of the neuronal cells expressing TDP-43 was reduced by oxidative stress, and edaravone (≥10 μmol/L) protected in a concentration-dependent manner against the neurotoxic insult. Differential gene expression analysis revealed changes among pathways related to nuclear erythroid 2-related-factor (Nrf2)-mediated oxidative stress response in cells expressing TDP-43. In edaravone-treated cells expressing TDP-43, significant changes in gene expression were also identified among Nrf2-oxidative response, unfolded protein response, and autophagy pathways. In addition, the expression of genes belonging to phosphatidylinositol metabolism pathways was modified. These findings suggest that the neuroprotective effect of edaravone involves the prevention of TDP-43 misfolding and enhanced clearance of pathological TDP-43 in TDP-43 proteinopathy.

| S-EPMC9319738 | biostudies-literature

Mutant TDP-43 in Astrocytes Kills Motor Neurons in Rats through Neurotoxic Gain and Neuroprotective Loss in Astrocytes

Project description:Mutation in TDP-43 is causative to amyotrophic lateral sclerosis (ALS). TDP-43 is a multifunctional ribonucleoprotein and is reproted to regulate thousands of genes in neurons, but how astrocytes contribute to TDP-43 pathogenesis is not known. This study examined how mutant TDP-43 in astrocytes kills motor neurons and causes ALS phenotypes. Primary astrocytes were isolated from transgenic rats expressing mutant TDP-43 or from control rats without mutant TDP-43 expression. Cultured astrocytes were induced to express mutant human TDP-43 and their gene expression profiles were determined by microarray assays. Microarray analysis revealed that hundreds of genes were altered in astrocytes in response to mutant TDP-43 expression. As mutant TDP-43 transgene is under the control of tetracycline-regulated pomoter elements (TRE), mutant TDP-43 expression is subjected to Doxycline regulation. Astrocytes isolated from GFAP-tTA/TRE-TDP43M337V rats were desiginated as M337V groups and astrocytes isolated from GFAP-tTA single transgenic rats were desiginated as tTA control groups. Total RNA was isolated from cultured astrocytes at varying times (3, 4, or 6 days after Dox withdrawal) after mutant TDP-43 was induced in astrocytes. Upon mutant TDP-43 induction in astroyctes, gene expression profiles in astroyctes were determined by Illumina Direct Hybridization Assay and compared between tTA and M337V groups at the varying time points of mutant TDP-43 induction.

2013-05-20 | E-GEOD-42091 | biostudies-arrayexpress

Transcriptomic evaluation of tau and TDP-43 synergism shows tauopathy predominates.

Project description:Cellular responses to co-morbid tau and TDP-43 preceding neurodegeneration have not been characterized. In this study, we evaluate transcriptomic changes at time-points preceding frank neuronal loss using a C. elegans model of tau and TDP-43 co-expression. We find significant differential expression and exon usage in genes enriched in multiple pathways including lipid metabolism and lysosomal degradation. We note that tau related changes largely resemble tau/TDP-43 changes. We test loss-of-function mutations in a subset of tau and TDP-43 responsive genes, identifying new modifiers of neurotoxicity. Characterizing early cellular responses to tau and TDP-43 co-pathology is critical for understanding protective and pathogenic responses to mixed proteinopathies, and an important step in developing therapeutic strategies protecting against pathological tau and TDP-43 in AD.

2024-03-15 | GSE249339 | GEO

Transcriptomic characterization of in vitro human iPSC-derived motor neuron systems for the exploration of cell autonomous mechanisms and modifiers of TDP-43 perturbation associated neurotoxicity

Project description:Transactive Response DNA-binding protein 43 (TDP-43) is a multifunctional nuclear protein ubiquitously expressed in all tissues. Although it is primarily nuclear, Amyotrophic Lateral Sclerosis (ALS) patients frequently present with cytoplasmic aggregates of TDP-43 in motor neurons on post-mortem examination. Although only about 5% of all ALS patients have a TARDBP mutation (Ghasemi and Brown 2018; Ingre et al. 2015), which is known to cause these insoluble cytoplasmic aggregates, 97% of ALS patients will develop cytoplasmic, insoluble TDP-43 aggregates regardless of whether they have a mutation in TARDBP or not (Ling et al. 2013). Overexpression of wild-type TDP-43 has previously been shown to be a valid model of inducing neurotoxicity as well as a limited amount of cytoplasmic re-localization and aggregation characteristic of ALS (Elden et al. 2010; Wils et al. 2010). In the search for modifiers of toxicity as conferred by TDP-43 overexpression in these models, knockout of Ataxin-2 (ATXN2) was proposed as a protective intervention in the context of TDP-43 perturbation in non-human model systems (Elden et al. 2010, Becker et al. 2017). This promising finding had not previously been validated in a human motor neuron system, nor had a thorough investigation been conducted to determine the mechanism of neuroprotection that ATXN2 knockout employs to drive the therapeutic effect. This sequencing study examines both ATXN2 intact and ATXN2 knockout motor neurons in the context of TDP-43 perturbation to explore global transcriptomic changes that arise from these changes in cellular state that are associated with progression of ALS (ATXN2 intact) and what pathways could be implicated in protection from ALS-associated neurodegeneration (ATXN2 Knockout).

2024-03-23 | GSE261875 | GEO

U373MG edaravone and carnosic acid

Project description:U373MG edaravone and carnosic acid

| PRJNA529669 | ENA

Mutant TDP-43 in Astrocytes Kills Motor Neurons in Rats through Neurotoxic Gain and Neuroprotective Loss in Astrocytes

2013-05-20 | GSE42091 | GEO