Mus musculus breed:C57BL/6
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA293372 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2178990.fastq.gz | Fastqsanger.gz | |||
| SRR2178991.fastq.gz | Fastqsanger.gz | |||
| SRR2178982.fastq.gz | Fastqsanger.gz | |||
| SRR2178992.fastq.gz | Fastqsanger.gz | |||
| SRR2178943.fastq.gz | Fastqsanger.gz |
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Project description:Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, with an incidence of around 1 in 6,000-10,000 live births. SMA is caused by low levels of full-length survival of motor neuron protein (SMN). We demonstrate that SMN binds to ribosomes and that this interaction is tissue-dependent. We performed ribosome profiling analyses on lysates from P5 wild-type mouse brains exposed to RNase I, from which we isolated SMN-primed ribosomes by immunoprecipitation. SMN-primed ribosomes are preferentially positioned within the first five codons of a set of mRNAs which are enriched for translational enhancer sequences in the 5’UTR and rare codons at the beginning of their coding sequence. These SMN-specific mRNAs are associated with neurogenesis, lipid metabolism, ubiquitination, chromatin regulation and translation. Additionally, we analyzed the positioning of active ribosomes using the Active-RiboSeq method based on RiboLace and compared early symptomatic SMA mouse brains to age-matched controls. We found that loss of SMN induces ribosome depletion, especially at the beginning of the coding sequence of SMN-specific mRNAs, leading to impairment of proteins involved in motor neuron function and stability. Keywords: motor neuron disease, spinal muscular atrophy, SMA, SMN, SMN1, survival of motor neuron, SMN-primed ribosome profiling, translation, RiboLace, Ribo-Seq, active translation, ribosome heterogeneity
2020-08-11 | GSE154106 | GEO
Project description:Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, with an incidence of around 1 in 6,000-10,000 live births. SMA is caused by low levels of full-length survival of motor neuron protein (SMN). Approximately 95% of SMA cases in humans are caused by homozygous deletion of SMN1, with a smaller number caused by discrete mutations within the gene. In concert with other RNA binding proteins, SMN forms complexes both in the nucleus and the cytoplasm of neurons. As such, SMN protein has housekeeping roles in the assembly of ribonucleoprotein (RNP) complexes. In addition, SMN localises to dendrites, synapses and axons in vivo and in vitro, where it is part of messenger RNP (mRNP) complexes with well-known roles in the transport of mRNA. These cellular processes are tightly linked to local translation, suggesting that SMN may play a pivotal role in its regulation. We employed next generation sequencing (NGS) to identify and quantify RNAs associated with polysomes (POL-Seq) in parallel with total cytoplasmic RNA (RNA-Seq) in an established mouse model of severe SMA at both early and late-symptomatic stages. This approach enables the simultaneous identification of variations in RNA populations at both translatome (RNAs engagement with polysomes) and transcriptome (steady state cytoplasmic RNAs) levels. Keywords: motor neuron disease, spinal muscular atrophy, SMA,SMN, translation, polysome profiling, POL-Seq, RNA-Seq
2017-10-24 | GSE102204 | GEO
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
Project description:Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in the survival of motor neuron (SMN) gene. Although the primary manifestation of SMA is degeneration of motor neurons in a dying-back manner, deficient SMN intrinsic to motor neurons does not cause severe motor neuron loss, as is the case in SMA mouse models. Thus, the involvement of non-neuronal cells in the pathogenesis of SMA has been suggested. Here, we report that a novel subset of fibro-adipogenic progenitors expressing Dpp4 (Dpp4+ FAPs) is required for the survival of motor neurons, in which BRCA1-associating protein 1 (Bap1) is crucial for the stabilization of SMN by preventing its ubiquitination-dependent degradation. Inactivation of Bap1 in FAPs decreased SMN levels and accompanied degeneration of the neuromuscular junction, leading to dying-back loss of motor neurons and muscle atrophy, reminiscent of SMA pathogenesis. Overexpression of ubiquitination-resistant SMN variant, SMNK186R, in Bap1-null FAPs completely prevented neuromuscular degenerations. In addition, transplantation of Dpp4+ FAPs, but not Dpp4- FAPs, completely rescued neuromuscular defects in the mutant mice. Our data revealed that Bap1-mediated stabilization of SMN in Dpp4+ FAPs is crucial for the survival of motor neurons and provided a new therapeutic approach to treat SMA.
2022-06-30 | GSE190426 | GEO
Project description:Pre-symptomatic development of lower motor neuron connectivity in a mouse model of severe spinal muscular atrophy
2009-12-07 | E-MEXP-2428 | biostudies-arrayexpress
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
Project description:Neuronal function critically depends on coordinated subcellular distribution of mRNAs. Disturbed mRNA processing and axonal transport has been found in spinal muscular atrophy and could be causative for dysfunction and degeneration of motoneurons. Despite the advances made in characterizing the transport mechanisms of several axonal mRNAs, an unbiased approach to identify the axonal repertoire of mRNAs in healthy and degenerating motoneurons has been lacking. Here we used compartmentalized microfluidic chambers to investigate the somatodendritic and axonal mRNA content of cultured motoneurons by microarray analysis. In axons, transcripts related to protein synthesis and energy production were enriched relative to the somatodendritic compartment. Knockdown of Smn, the protein deficient in spinal muscular atrophy, produced a large number of transcript alterations in both compartments. Transcripts related to immune functions, including MHC class I genes, and with roles in RNA splicing were upregulated in the somatodendritic compartment. On the axonal side, transcripts associated with axon growth and synaptic activity were downregulated. These alterations provide evidence that subcellular localization of transcripts with axonal functions as well as regulation of specific transcripts with nonautonomous functions is disturbed in Smn-deficient motoneurons, most likely contributing to the pathophysiology of spinal muscular atrophy.
2014-12-01 | GSE59506 | GEO
Project description:Spinal muscular atrophy (SMA) due to loss-of-function of SMN protein is associated with severe loss of voluntary muscle control and is a leading inherited cause of infant mortality. SMA treatments will benefit from in-depth knowledge of functional pathways disrupted in disease and identification of SMN modulators. Here, we present a comprehensive temporal profile of proteogenomic expression patterns in developing mouse spinal cords (Δ7 model), alongside endpoint analyses of human spinal and ventral root tissues in SMA disease, identifying targets for assessing disease progression and treatment response. SMA disease results in development-associated deficiencies in transcription, translation initiation, intracellular transport, and protein folding, and diminished RNA translation efficiency for proteins important in axon development/myelination. The broad impact of SMN deficiency prompted the search for co-regulated proteins that modulate SMN protein levels, resulting in identification of the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin ligase as a potential modulator of SMN protein stability. Functional studies of APC/C showed that both SMN and HuD are specific interactors of the APC/C in neurons and that selective APC/C inhibition significantly limited SMN and HuD degradation. Finally, we demonstrate that APC/C inhibition rescues motor axon defects characteristic of SMA in a zebrafish model of SMA disease.
2022-01-18 | GSE128129 | GEO
Project description:The C-terminal domain (CTD) of the RNA polymerase II (RNAPII) subunit POLR2A is a platform for modifications specifying the recruitment of factors that regulate transcription, mRNA processing, and chromatin remodeling. Here, we show that a CTD arginine residue (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires Protein Arginine Methyltransferase 5 (PRMT5) and recruits the Tudor domain of the Survival of Motor Neuron (SMN) protein, which is mutated in spinal muscular atrophy (SMA). SMN interacts with Senataxin, which is sometimes mutated in Ataxia Oculomotor Apraxia 2 (AOA2) and Amyotrophic Lateral Sclerosis (ALS4). Because R1810me2s and SMN, like Senataxin, are required for resolving RNA-DNA hybrids, created by RNA polymerase II, that form â??R-loopsâ?? in transcription termination regions, we propose that R1810me2s, SMN, and Senataxin are components of a pathway for R-loop resolution in which defects can influence transcription termination and may contribute to neurodegenerative disorders. ChIP of RNAPII in Raji cells expressing shRNG against SMN or GFP; ChIP against RNAPII in Raji cells where endogenous RNAPII has been replaced with wt or R1810A mutant amanitin-resistant protein; and ChIP of SMN in HEK293 cells.
2015-12-31 | E-GEOD-73379 | biostudies-arrayexpress
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