Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

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

PROVIDER: PRJNA343962 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR4291470_1.fastq.gz	Fastqsanger.gz
	SRR4291470_2.fastq.gz	Fastqsanger.gz
	SRR4291480_1.fastq.gz	Fastqsanger.gz
	SRR4291480_2.fastq.gz	Fastqsanger.gz
	SRR4291490_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 190

Similar Datasets

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

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

Neurochondrin interacts with the SMN protein suggesting a novel mechanism for Spinal Muscular Atrophy pathology.

Project description:Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative condition caused by reduction in functional Survival Motor Neurones Protein (SMN). SMN has been implicated in transport of mRNA in neural cells for local translation. We previously identified microtubule-dependant mobile vesicles rich in SMN and SmB, a member of the Sm family of snRNP-associated proteins, in neural cells. By comparing the interactomes of SmB and SmN, a neural-specific Sm protein, we now show that the essential neural protein neurochondrin (NCDN) interacts with Sm proteins and SMN in the context of mobile vesicles in neurites. NCDN has roles in protein localisation in neural cells, and in maintenance of cell polarity. NCDN is required for the correct localisation of SMN, suggesting they may both be required for formation and transport of trafficking vesicles. NCDN may have potential as a therapeutic target for SMA together with, or in place of, those targeting SMN expression

2018-03-15 | PXD008710 | Pride

Prenatal SMN-dependent defects in translation uncover a reversible primary ciliopathy in spinal muscular atrophy

Project description:Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein resulting from mutations in the SMN1 gene. Several therapeutic approaches capable of boosting SMN are now approved for use in human patients, delivering remarkable improvements in lifespan and symptom severity. However, new and unexpected phenotypes are being reported in treated SMA patients, including growing evidence for significant neurodevelopmental comorbidities in some individuals, indicative of alterations in brain development. Here, using a mouse model of severe SMA, we reveal an underlying neurodevelopmental phenotype in SMA where prenatal SMN-dependent defects in translation drive a primary ciliopathy in the CNS. Cell proliferation was significantly reduced in the hippocampus of SMA mice at E14.5, accompanied by widespread perturbations in translation, disrupting genes associated with primary cilia. The density of primary cilia in vivo, as well as cilial length in vitro, was significantly decreased in prenatal SMA mice, revealing core morphological hallmarks of a primary ciliopathy. Prenatal transplacental therapeutic intervention with an SMN-restoring small molecule (Risdiplam) rescued primary cilia defects in SMA mouse embryos. We conclude that SMN protein is required for normal cellular and molecular development of the CNS, with low levels in SMA driving a primary ciliopathy. Early, systemic treatment with SMN-restoring therapies is likely to be required to target neurodevelopmental comorbidities.

2025-09-01 | GSE295681 | GEO

Widespread intron retention and exon skipping characterise alternative splicing changes in a C. elegans model of spinal muscular atrophy

Project description:Widespread intron retention and exon skipping characterise alternative splicing changes in a C. elegans model of spinal muscular atrophy

| PRJEB101991 | ENA

KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS

Project description:Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

2026-03-11 | GSE302774 | GEO

Transcription profiling by array of denervated muscular atrophy

Project description:To elaborate the process of denervated muscular atrophy, and provide scientific basis for the prevention and treatment of denervated muscular atrophy. we performed a time course transcriptomic analysis of denervated muscular atrophy

2019-06-16 | E-MTAB-8009 | biostudies-arrayexpress

Trancriptional regulation by axonal SMN on motor neuron cells

Project description:Muscular atrophy (SMA) is an autosomal recessive disease causing selective motor neuron death by the loss of telomeric survival motor neuron gene, SMN1. Axonal SMN, a-SMN, is a truncated form of SMN, derived from an alternatively spliced SMN1 gene. (Setola, et. al. 2007 PNAS 104, 1959-1964). The cellular clones expressing a-SMN in a tetracycline-dependent manner were isolated from NSC34 by two-step stable transfection, first with the tetracycline-repressor construct and subsequently with the a-SMN cDNA. To identify novel a-SMN target genes, the transcriptome of several a-SMN clones was analyzed and compared with that of parental cells.

2012-01-07 | E-MEXP-3402 | biostudies-arrayexpress

Pathologic alteration in the proteome of synaptosomes from the mouse model of spinal muscular atrophy

Project description:In this study, label-free quantitative proteomic analysis was performed using the Smn 2B/- mouse model to identify and investigate significant changes in protein abundance that may be related to the pathogenesis and neurodegeneration oberved in spinal muscular atrophy (SMA)

2019-07-04 | PXD012850 | Pride

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