Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA825077 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18693927_1.fastq.gz | Fastqsanger.gz | |||
| SRR18693927_2.fastq.gz | Fastqsanger.gz | |||
| SRR18693928_1.fastq.gz | Fastqsanger.gz | |||
| SRR18693928_2.fastq.gz | Fastqsanger.gz | |||
| SRR18693929_1.fastq.gz | Fastqsanger.gz |
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Project description:Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). To identify additional ways of reducing ataxin-2 levels, we performed a genome-wide screen in human cells for regulators of ataxin-2 and identified RTN4R, the gene encoding the RTN4/NoGo-Receptor, as a top hit. This dataset contains the RNA-sequencing data used to support the conclusions from this study.
2022-10-18 | GSE200530 | GEO
Project description:ATXN2 has emerged as an exciting therapeutic target for neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2), as lowering its levels via genomic knockout or anti-sense oligonucleotide (ASO) treatment has been shown to mitigate disease phenotypes and led to a current clinical trial of ATXN2 ASOs for treatment of ALS in humans. To identify additional ways to lower ataxin‑2 protein levels, we performed a genome-wide fluorescence activated cell sorting (FACS)-based CRISPR screen in human cells and identified multiple components of the lysosomal vacuolar ATPase (v‑ATPase) as modifiers of ataxin‑2 levels. This dataset contains the RNA-sequencing data and CRISPR screen data used to support the conclusions from this study.
2022-10-18 | GSE189417 | GEO
Project description:Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). Additional strategies to lower levels of ataxin-2 could be beneficial. Here, we perform a genome-wide arrayed small interfering RNA (siRNA) screen in human cells and identify RTN4R, the gene encoding the RTN4/NoGo-Receptor, as a potent modifier of ataxin-2 levels. RTN4R knockdown, or treatment with a peptide inhibitor, is sufficient to lower ataxin-2 protein levels in mouse and human neurons in vitro, and Rtn4r knockout mice have reduced ataxin-2 levels in vivo. We provide evidence that ataxin-2 shares a role with the RTN4/NoGo-Receptor in limiting axonal regeneration. Reduction of either protein increases axonal regrowth following axotomy. These data define the RTN4/NoGo-Receptor as a novel therapeutic target for ALS and SCA2 and implicate the targeting of ataxin-2 as a potential treatment following nerve injury.
| S-EPMC9664481 | biostudies-literature
Project description:Nogo, also called RTN4, functions through three isoforms including Nogo-A, -B, and -C. Although Nogo-A is a well-known CNS inhibitor and the level of Nogo-A is increased in muscles of ALS patients, its role in the regulation of skeletal muscle homeostasis and regeneration is still vague. In this study, we analyzed various pathological muscle condition of human and mouse model, and discovered significant increase of Nogo-A and myogenic factors. To understand the role of Nogo in skeletal muscle, muscle transcripts from Nogo+/+ and Nogo-/- mouse were analyzed and observed intensified gene expression involved in adipocyte differentiation and lipid metabolism, and reduced gene expression related to muscle differentiation and structure organization suggesting muscle disorder from muscle replacement with fat deposition. Skeletal muscle structure from Nogo null mice displayed dystrophic phenotypes including impaired myofiber structure and immune cell infiltrations, and dysregulated homeostatic features such as higher level of MyoD, procaspase 3, CHOP, and AKT compared to wild-type muscle. Notexin-injured Nogo deficient muscle resulted higher level of immune cell infiltration but defective in IL-6 production, a well-known myokine from immune cells, and abnormally upregulated regenerative muscle fibers than normal muscle. Therefore we hypothesized that increased Nogo-A in pathological conditions may regulate muscle regeneration. Then differentiating C2C12 cells and induced myogenic stem cells(iMSC) showed upregulated Nogo-A and Myogenin, and Nogo-A silencing in C2C12 cells abrogated the capability to differentiate into myotubes. In conclusion, Nogo functions to maintain muscle homeostasis and integrity, and altered Nogo-A expression in pathological muscle condition mediates muscle regeneration. These understanding suggests Nogo-A as a novel differentiation target for the treatment of myopathies at clinical set.
2019-05-31 | GSE131955 | GEO
Project description:Ataxin-2 is a conserved translational control protein as well as an important target for ALS therapeutics under development. Despite its clinical and biological significance, Ataxin-2’s activities, mechanisms and functions are not well understood. Using Drosophila Ataxin-2 (Atx2) we investigate how Ataxin-2 IDRs work with structured (Lsm, Lsm-AD and PAM2) domains to enable positive and negative regulation of target mRNAs. Using TRIBE (Targets of RNA-Binding Proteins Identified by Editing) technology, we identified and analysed Atx-2 target mRNAs in the Drosophila brain.
2021-03-03 | GSE153985 | GEO
Project description:Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2
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Project description:The elevation of Nogo-B expression in T2DM mice and Nogo-B knockdown alleviated diabetic symptoms in db/db mice prompted us to further investigate the involvement of Nogo-B in the insulin signaling pathway and T2DM. The three isoforms of Nogo are derived from various RNA splicing events, so deleting Nogo-B exons 2-4 results in the deficiency of other Nogo members, resulting in Nogo knockout (Nogo-/-) mice. As the liver is the key organ in the systemic response to insulin and controls glucose and lipid metabolism, we conducted RNA-seq of livers isolated from 8-week-old Nogo-/- mice and WT littermates.
2023-07-24 | GSE236979 | GEO
Project description:Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) functions in translational regulation, mRNA stability, and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which mediates translational activation of some target mRNAs, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments on Drosophila and human Ataxin-2 proteins. Results of Targets of RNA-Binding Proteins Identified by Editing (TRIBE) experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA content of Ataxin-2 mRNP granules. Co-localization and co-immunoprecipitation analyses show that structured interactions between Ataxin-2 and PABP additionally help determine protein components of Ataxin-2-associated mRNP granules and contribute to Ataxin-2’s association with stress granules. Finally, in vivo experiments in Drosophila indicate that while the Atx2-LSm domain protects against neurodegeneration, structured PAM2- and unstructured IDR- interactions both promote degeneration. Taken together the data: (a) lead to a proposal for how Ataxin-2 interactions are remodelled during different stages of translational control; (b) show how structured and non-structured interactions of Ataxin-2 contribute differently to the specificity and efficiency of RNP granule condensation; and (c) demonstrate that the Ataxin-2 protein contains multiple activities that may respectively prevent or promote neurodegeneration.
2024-04-22 | GSE196739 | GEO
Project description:In order to determine if there are any genetic differences among lungs of Nogo-A/B knockout mice which may explain their enhanced asthmatic-like responses, we have employed whole genome microarray expression profiling as a discovery platform to identify any genes that may be altered in the lung of Nogo-A/B knockout mice. RNA was isolated from three biological replicates of mouse lungs from naive WT and Nogo-A/B Knockout mice and run on agilent array. Two genes was significantly altered in Nogo-A/B Knockout lungs, SPLUNC1 and RTN4 (Nogo) which was significantly decreased and confirmed by real-time PCR.
2010-10-20 | GSE24218 | GEO
Project description:In order to determine if there are any genetic differences among lungs of Nogo-A/B knockout mice which may explain their enhanced asthmatic-like responses, we have employed whole genome microarray expression profiling as a discovery platform to identify any genes that may be altered in the lung of Nogo-A/B knockout mice. RNA was isolated from three biological replicates of mouse lungs from naive WT and Nogo-A/B Knockout mice and run on agilent array. Two genes was significantly altered in Nogo-A/B Knockout lungs, SPLUNC1 and RTN4 (Nogo) which was significantly decreased and confirmed by real-time PCR. Gene expression in naïve mouse lungs of WT and Nogo-A/B knockout mice was measured in three individual biological replicates from each group.
2010-10-20 | E-GEOD-24218 | biostudies-arrayexpress