Targeted ASO-mediated Atp1a2 knockdown in astrocytes reduces SOD1 aggregation and accelerates disease onset in mutant SOD1 mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA807521 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18048405_1.fastq.gz | Fastqsanger.gz | |||
| SRR18048405_2.fastq.gz | Fastqsanger.gz | |||
| SRR18048406_1.fastq.gz | Fastqsanger.gz | |||
| SRR18048406_2.fastq.gz | Fastqsanger.gz | |||
| SRR18048407_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 78 |
Similar Datasets
Project description:Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases.
2023-11-30 | GSE196843 | GEO
Project description:Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases.
| S-EPMC10683999 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the selective loss of motor neurons. Mutations in Cu/Zn superoxide dismutase (SOD1) are the second most common cause of ALS and it is now well accepted that they result in a gain of toxicity due to protein misfolding. We previously demonstrated in the SOD1G93A rat model that misfolded SOD1 exists as distinct conformers and deposits on mitochondrial subpopulations. Here, using SOD1G93A rats coupled with conformation-restricted antibodies for misfolded SOD1 (AMF7-63 and B8H10), we identified the interactomes of the mitochondrial pools of misfolded SOD1. This strategy identified binding partners that uniquely interacted with either AMF7-63- or B8H10-reactive SOD1 conformers as well as a high proportion of interactors common to both conformers. Of this latter set, we identified the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) and determined that exposure of the SOD1 functional loops facilitates this interaction. However, this conformational criterion is not universally fulfilled by all SOD1 mutants and differentiates TRAF6-interacting from non-interacting SOD1 mutants. Functionally, TRAF6 stimulates mutant SOD1 polyubiquitination and aggregation. While TRAF6 E3 ubiquitin ligase activity is required for the former, it is dispensable for the latter, indicating that the polyubiquitination and aggregation of mutant SOD1 mediated by TRAF6 are independent events. We propose that misfolded SOD1 binding to TRAF6 may be relevant to ALS disease.
2020-02-24 | PXD015279 | Pride
Project description:Recent genetic studies of ALS patients have identified several forms of ALS that are associated with mutations in RNA binding proteins. In animals or cultured cells, such defects broadly affect RNA metabolism. This raises the question of whether all forms of ALS have general effects on RNA metabolism. We tested this hypothesis in a mouse model of ALS that is transgenic for a human disease-causing mutation in the enzyme superoxide dismutase 1 (SOD1). We analyzed RNA from laser-captured spinal cord motor neuron cell bodies of the mutant SOD1 strain, comparing the RNA profile with that from a corresponding wild-type SOD1 transgenic strain. We prepared the samples from animals that were presymptomatic, but which manifested abnormalities at the cellular level that are seen in ALS, including aggregation of the mutant protein in motor neuron cell bodies and defective morphology of neuromuscular junctions, the connections between neuron and muscle. We observed only minor changes in the level and splicing of RNA in the SOD1 mutant animals as compared with wild-type, suggesting that mutant SOD1 produces the toxic effects of ALS by a mechanism that does not involve global RNA disturbance. RNA-Seq of laser microdissection of motor neuron bodies from two biological replicates each of SOD1 YFP (wildtype 592) and SOD1 G85R YFP (737) transgenic mice.
2012-12-04 | E-GEOD-38820 | biostudies-arrayexpress
Project description:DNA sequence variants in the TBK1 gene associate with or cause sporadic or familial amyotrophic lateral sclerosis (ALS). Here we show that mice bearing human ALS-associated TBK1 missense loss-of-function mutations, or mice in which the Tbk1 gene is selectively deleted in motor neurons, do not display a neurodegenerative disease phenotype. However, loss of TBK1 function in motor neurons of the SOD1G93A mouse model of ALS impairs autophagy, increases SOD1 aggregation, and accelerates early disease onset without affecting lifespan. By contrast, point mutations that decrease TBK1 kinase activity in all cells also accelerate disease onset but extend the lifespan of SOD1 mice. This difference correlates with the failure to activate high levels of expression of interferon-inducible genes in glia. We conclude that loss of TBK1 kinase activity impacts ALS disease progression through distinct pathways in different spinal cord cell types and further implicate the importance of glia in neurodegeneration.
2020-04-13 | GSE146141 | GEO
Project description:Recent genetic studies of ALS patients have identified several forms of ALS that are associated with mutations in RNA binding proteins. In animals or cultured cells, such defects broadly affect RNA metabolism. This raises the question of whether all forms of ALS have general effects on RNA metabolism. We tested this hypothesis in a mouse model of ALS that is transgenic for a human disease-causing mutation in the enzyme superoxide dismutase 1 (SOD1). We analyzed RNA from laser-captured spinal cord motor neuron cell bodies of the mutant SOD1 strain, comparing the RNA profile with that from a corresponding wild-type SOD1 transgenic strain. We prepared the samples from animals that were presymptomatic, but which manifested abnormalities at the cellular level that are seen in ALS, including aggregation of the mutant protein in motor neuron cell bodies and defective morphology of neuromuscular junctions, the connections between neuron and muscle. We observed only minor changes in the level and splicing of RNA in the SOD1 mutant animals as compared with wild-type, suggesting that mutant SOD1 produces the toxic effects of ALS by a mechanism that does not involve global RNA disturbance.
2012-12-04 | GSE38820 | GEO
Project description:Mutations in superoxide dismutase 1 (SOD1) are a major cause of familial amyotrophic lateral sclerosis (ALS), whereby the mutant proteins misfold and aggregate to form intracellular inclusions. We report that both small ubiquitin-like modifier (SUMO) 1 and SUMO2/3 modify ALS-linked SOD1 mutant proteins at lysine 75 in a motoneuronal cell line, the cell type affected in ALS. In these cells, SUMO1 modification occurred on both lysine 75 and lysine 9 of SOD1, and modification of ALS-linked SOD1 mutant proteins by SUMO3, rather than by SUMO1, significantly increased the stability of the proteins and accelerated intracellular aggregate formation. These findings suggest the contribution of sumoylation, particularly by SUMO3, to the protein aggregation process underlying the pathogenesis of ALS.
| S-EPMC4074151 | biostudies-literature
Project description:Synucleinopathies are triggered by the aggregation of α-synuclein (αSyn), leading to progressive neurodegeneration. However, the intracellular mechanism of αSyn aggregation remains unclear. Here we show that assembly of RNA G-quadruplexes (rG4s) form scaffolds for αSyn aggregation, contributing to neurodegeneration. Purified αSyn binds rG4s directly through the N-terminus. rG4 itself undergoes phase separation and assembly by Ca2+, accelerating the sol-gel phase transition of αSyn. In αSyn preformed fibrils (PFF)-treated neurons, rG4s assembly composed of synaptic mRNAs co-aggregates with αSyn upon Ca2+ excess influx into cytoplasm, eliciting synaptic dysfunction. Artificial assembly of rG4s using an optogenetic approach evokes αSyn aggregation and neuronal dysfunction. Administration of 5-aminolevulinic acid (5-ALA), a prodrug of protoporphyrin IX (PpIX) that prevents phase separation of rG4s, attenuating αSyn aggregation, neurodegeneration, and progressive motor deficits in PFF-injected synucleinopathy mice. Together, assembly of rG4s due to dysregulation of intracellular Ca2+ homeostasis accelerates αSyn phase transition and aggregation may contribute to pathogenesis of synucleinopathies.
2023-07-18 | GSE234238 | GEO
Project description:To gain more insights into the functional significance of lnc-HLX-2-7, gene expression profiles were measured using D425 (sh-CTRL), D425 (sh-HLX) and intracranial D425 xenografts treated with ASO-CTRL and ASO-lnc-HLX 2-7 by RNA sequencing.
2023-11-01 | GSE188746 | GEO
Project description:Transcriptional profiling of mouse liver comparing control, scrambled-oligonucleotides (Cont)-treated mice with Perilipin 2-antisense oligonucleotides (Plin2-ASO)-treated mice. C57BL/6 mice on a high-fat diet were treated with oligonucleotides in vivo. The goal was to determine the effects of Plin2 down-regulation in the liver on global gene expression. Two-condition experiment, control oligonucleotides vs. Plin2-antisense oligonucleotides. Biological replicates: 4 control replicates, 4 Plin2-ASO replicates.
2012-12-05 | E-GEOD-37011 | biostudies-arrayexpress