Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Rational targeting of RNA structure in SMN2 transcripts reverses Spinal Muscular Atrophy molecular phenotypes

ABSTRACT: Marine natural compound homocarbonyltopsentin PK4C9 is a small TSL2-binding molecule which was identified to increase exon 7 splicing to therapeutic levels and rescue downstream molecular alterations in SMA cells. To assess the functionality of the restored SMN protein, we studied whether PK4C9 could modify SMN-mediated splicing events using RNA sequencing data from PK4C9-treated (40 microM, 24 h) vs. DMSO-treated GM03813C fibroblasts. The data was also used to find shared motifs amongst PK4C9-sensitive splicing events, in order to contribute to the description of the mechanism of action of PK4C9 and to help identify off-targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94111 | GEO | 2018/03/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

Project description:Characterization of the selectivity of SMN splicing modifiers in SMA type I fibroblasts by RNASeq In total 12 samples were analyzed, divided into four distinct groups (treated with SMN-C3 @ 500 nM; controls for SMN-C3; treated with SMN-C1 @ 100 nM; controls for SMN-C1) containing 3 replicates each.

2014-10-22 | E-GEOD-62540 | biostudies-arrayexpress

SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

Project description:Characterization of the selectivity of SMN splicing modifiers in SMA type I fibroblasts by RNASeq

2014-10-22 | GSE62540 | GEO

Expression profiles of skeletal muscle from Taiwanese Smn-/-;SMN2 spinal muscular atrophy mouse model treated with Pip6a-PMO

Project description:Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple and parallel data driven approaches for the development of novel treatments for use in combination with SMN restoration therapies.

2020-05-14 | GSE150517 | GEO

Spinal Muscular Atrophy Patient iPSC-derived Motor Neurons Display Altered Proteins at Early Stages of Differentiation

Project description:Spinal muscular atrophy (SMA) is characterized by low levels of survival motor neuron (SMN) protein and loss of motor neurons (MN); however, the underlying mechanism that links SMN deficiency to selective motor neuronal dysfunction is still largely unknown. We present here, for the first time, a comprehensive quantitative mass spectrometry study that covers the development of iPSC-derived MNs from both healthy individuals and SMA patients. We show an altered proteomic signature in SMA already at early stages during MN differentiation, associated with ER to Golgi transport, mRNA splicing and protein ubiquitination, in line with known SMA phenotypes. These alterations in the SMA proteome increase further towards later stages of MN differentiation. In addition, we find differences in altered protein expression between SMA patients, which however, have similar biological functions. Finally, we highlight several known SMN-binding partners as well as proteins associated with ubiquitin-mediated proteolysis and evaluate their expression changes during MN differentiation. Altogether, our work provides a rich resource of molecular events during early stages of MN differentiation, containing potentially therapeutically interesting protein expression profiles for SMA.

2022-02-15 | PXD015115 | Pride

SMN deficiency in spinal muscular atrophy causes widespread intron retention and DNA damage

Project description:Spinal muscular atrophy is the leading genetic cause of infant mortality and is caused by homozygous loss of the SMN1 gene. We investigated global transcriptome changes in the spinal cord of inducible SMA mice. SMN depletion caused widespread retention of introns with weak splice sites or belonging to the minor (U12) class. We further demonstrated accumulation of DNA double strand breaks in the spinal cord of SMA mice and in human SMA cell culture models. DNA damage was partially rescued by suppressing the formation of R-loops, which accumulated over retained introns. We propose that instead of single gene effects, pervasive splicing defects caused by SMN deficiency trigger a global DNA damage and stress response, thus compromising motor neuron survival.

2017-03-21 | GSE87281 | GEO

SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy

Project description:<p>Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DβH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA. </p>

2023-11-27 | MTBLS8784 | MetaboLights

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for Spinal Muscular Atrophy

Project description:RNA-seq analysis of Drosophila snRNP biogenesis mutants. In brief, the Phax and Ars2 mutant RNA-seq was used in combination with Series GSE49587 (Smn mutant and wild-type Oregon-R RNA-seq) to classify transcriptome changes as snRNP-dependent or mutant specific. Additional flies with Smn transgenes, containing Smn mutations that cause Spinal Muscular Atrophy (SMA) in humans, were then used to determine whether the snRNP-dependent or mutant specific changes were present in intermediate models of SMA.

2016-05-05 | GSE81121 | GEO

Transcriptome profiling of severe spinal muscular atrophy mouse embryonic stem cell-derived motor neurons

Project description:Proximal spinal muscular atrophy (SMA) is an early onset, autosomal recessive motor neuron disease caused by loss of or mutation in SMN1 (survival motor neuron 1). Despite understanding the genetic basis underlying this disease, it is still not known why motor neurons (MNs) are selectively affected by the loss of the ubiquitously expressed SMN protein. Using a mouse embryonic stem cell (mESC) model for severe SMA, the RNA transcript profiles (transcriptomes) between control and severe SMA (SMN2+/+;mSmn-/-) mESC-derived MNs were compared in this study using massively parallel RNA sequencing (RNA-Seq). The MN differentiation efficiencies between control and severe SMA mESCs were similar. RNA-Seq analysis identified 3094 upregulated and 6964 downregulated transcripts in SMA mESC-derived MNs when compared against control cells. Pathway and network analysis of the differentially expressed RNA transcripts showed that pluripotency and cell proliferation transcripts were significantly increased in SMA MNs while transcripts related to neuronal development and activity were reduced. The differential expression of selected transcripts such as Crabp1, Crabp2 and Nkx2.2 was validated in a second mESC model for SMA as well as in the spinal cords of low copy SMN2 severe SMA mice. Furthermore, the levels of these selected transcripts were restored in high copy SMN2 rescue mouse spinal cords when compared against low copy SMN2 severe SMA mice. These findings suggest that SMN deficiency affects processes critical for normal development and maintenance of MNs. RNA profiles were generated from FACS-purified control and SMA mESC-derived motor neurons (n=3/genotype) by deep sequencing using Illumina HighSeq 2500

2014-09-08 | E-GEOD-56284 | biostudies-arrayexpress

Suppression of NCALD protects against spinal muscular atrophy by restoring impaired endocytosis

Project description:Spinal muscular atrophy (SMA) is a common genetic motor neuron (MN) disease caused by low levels of the ubiquitously expressed housekeeping survival motor neuron (SMN) protein, whereas concomitant overexpression of plastin 3 (PLS3) protects from SMA. Here we identify neurocalcin delta (NCALD), a neuronal calcium sensor, as a second fully protective SMA modifier, which counteracts SMA pathology when downregulated. We show reduced Ca2+ influx and impaired endocytosis in SMA, which are crucial processes in synaptic vesicle recycling and neurotransmission. Remarkably, both reduced NCALD or increased PLS3 restore endocytosis in cell culture and MN function across species in zebrafish, worm and mouse SMA models, whereas Ca2+ influx remains disturbed. Furthermore, NCALD physically binds clathrin in a Ca2+-dependent manner. We propose that NCALD acts as a Ca2+-regulated inhibitor of endocytosis, and that endocytosis is critically affected in SMA. This finding opens new therapeutic avenues for SMA. Multifactorial design comparing affected patients and unaffected disease carriers against severly affected control group to identify disease modifying transcripts

2015-01-01 | E-GEOD-58316 | biostudies-arrayexpress

Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy

Project description:Spinal Muscular Atrophy (SMA) is a motor-neuron disease caused by mutations of the SMN1 gene. The human paralog SMN2, whose exon 7 (E7) is predominantly skipped cannot compensate for the lack of SMN1. Nusinersen is an antisense oligonucleotide that upregulates E7 inclusion and SMN protein levels by displacing the splicing repressors hnRNPA1/A2 from their target site in intron 7. We show that, by promoting transcriptional elongation, the histone deacetylase inhibitor VPA cooperates with nusinersen to promote E7 inclusion. Surprisingly, nusinersen promotes the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to PolII elongation that inhibits E7 inclusion. By removing the roadblock, VPA counteracts the undesired chromatin effects of nusinersen, resulting in higher E7 inclusion, without large pleiotropic effects, as assessed by genome-wide analyses. Combined administration of nusinersen and VPA in SMA mice strongly synergized in SMN expression, growth, survival, and neuromuscular function.

2022-06-09 | GSE167762 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data