SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE62540 | GEO | 2014/10/22
SECONDARY ACCESSION(S): PRJNA264368
REPOSITORIES: GEO
Similar Datasets
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
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
Project description: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.
2018-03-06 | GSE94111 | GEO
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
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
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.
2014-09-08 | GSE56284 | GEO
Project description:The deficiency of Survival motor neuron (SMN) protein causes the motor neuron disease spinal muscular atrophy (SMA). One of the cellular hallmarks of motor neuron diseases is the reduction in number of nuclear bodies (NBs) positive for the SMN protein. Owing to its ubiquitous expression, the consequences of SMN reduction can be studied in SMA patient fibroblasts. In previous studies, we described the beneficial effects of flunarizine on SMN-positive NBs both in fibroblasts of SMA patients and in spinal motor neurons of an SMA mouse model. Given that nuclear bodies are involved in RNA metabolism, here the goals are to make a proof-of-concept that genes modulated by flunarizine at the RNA levels can be identified and confirmed at the protein levels in SMA patient fibroblasts. Indeed, RNA-Seq analysis reveals that TXNIP is the most reduced by a 4-hr flunarizine treatment of SMA patient fibroblasts. This result is confirmed by RT-qPCR. Moreover, immunoblot analyses also shows a marked reduction of TXNIP at the protein levels in flunarizine-treated SMA fibroblasts.
2020-04-30 | GSE145146 | GEO
Project description:Spinal Muscular Atrophy (SMA) is typically characterized as a motor neuron disease, but extra-neuronal phenotypes are present in almost every organ in severely affected patients and animal models. Extra-neuronal phenotypes were previously underappreciated as patients with severe SMA phenotypes usually died in infancy; however, with current treatments for motor neurons which increase patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to new treatment-modified phenotypes. Fatty liver is seen in animal models of SMA, but generalizability to patients and whether this is due to hepatocyte-intrinsic Survival Motor Neuron (SMN) protein deficiency and/or subsequent to skeletal muscle denervation is unknown. If liver pathology in SMA is SMN-dependent and hepatocyte-intrinsic, this provides proof of concept that SMN repleting therapies must target extra-neuronal tissues as well as motor neurons for optimal patient outcome. Here we show that fatty liver is present in SMA and that SMA patient-specific iHeps are susceptible to steatosis. Using proteomics, functional studies and CRISPR/Cas9 gene editing, we confirm that fatty liver in SMA is a primary SMN-dependent hepatocyte-intrinsic liver defect associated with mitochondrial and other hepatic metabolism dysfunctions. These pathologies require monitoring and indicate the need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.
2024-05-09 | PXD045401 | JPOST Repository
Project description:Spinal Muscular Atrophy (SMA) is well-known to be caused by mutations in the gene Survival of Motor Neuron 1 (SMN1). Because this gene is ubiquitously expressed, it remains poorly understood why motor neurons (MNs) are one of the most affected cell types. To begin to address this question, we carried out RNA-sequencing studies using fixed, antibody-labeled and purified MNs produced from control and SMA patient-derived induced pluripotent stem cells (iPSCs). We found SMA-specific changes in MNs, including hyper-activation of the endoplasmic reticulum (ER) stress pathway and enhanced apoptosis. Functional studies demonstrated that inhibition of ER stress improves overall MN health and survival in vitro even in MNs with low SMN levels. In SMA mice, we show that systemic delivery of an ER stress inhibitor that crosses the blood-brain-barrier led to preservation of MNs in the spinal cord and prolonged survival of these mice. Therefore, our study implies that selective activation of ER stress underlies MN death in SMA. Moreover, the approach we have taken would be broadly applicable to studying disease-prone human cells in heterogeneous cultures. total RNA collected from ES cell and patient ES cell derived spinal motor neurons
2015-09-01 | E-GEOD-69175 | biostudies-arrayexpress
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