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Gene expression profiling of vulnerable spinal motor neurons in the SMNΔ7 mouse model of SMA upon modulation of p53 signaling

ABSTRACT: Selective motor neuron degeneration in spinal muscular atrophy (SMA) is driven by converging mechanisms that promote stabilization and phosphorylation of p53 in vulnerable motor neurons. However, the downstream transcriptional programs that execute motor neuron death remain incompletely defined.To characterize p53-associated transcriptional changes in vulnerable motor neurons, we performed RNA sequencing of cholera toxin subunit B (CTB)-labeled lumbar (L1–L3) motor neurons isolated by laser-capture microdissection from postnatal day 6 SMNΔ7 (SMNΔ7;SMN2;Smn−/−) SMA mice and wild-type littermate controls. Disease-associated gene expression changes were defined by comparison of SMA and wild-type motor neurons. To assess pathway-specific contributions, untreated SMA mice were compared to SMA mice treated with Pifithrin-α (inhibitor of p53 transcriptional activity), MW150 (p38 MAPK inhibitor that prevents p53 phosphorylation), or SMN-C3 (SMN splicing modifier). Differential gene expression analysis was performed using kallisto-based transcript quantification and DESeq2.

ORGANISM(S): Mus musculus

PROVIDER: GSE320428 | GEO | 2026/08/12

REPOSITORIES: GEO

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Gene expression profiling of LMC and MMC motor neurons in SMA mice

Project description:Spinal muscular atrophy (SMA) is a neurodegenerative disease which exhibits selective motor neuron death caused by a ubiquitous deficiency of the survival motor neuron (SMN) protein. It remains unclear how the ubiquitous reduction of SMN lead to death in selective motor neuron pools. Medial motor neuron columns (MMC) are vulnerable, whereas lateral motor columns (LMC) are resistant to motor neuron death in SMA. Here we performed microarray and pathway analysis comparing cholera toxin subunit B (CTb) labeled vulnerable MMC and resistant LMC of pre-symptomatic SMA with corresponding motor neuron columns of control mice to identify pathways involved in selective motor neuron death in SMA. WT is FVB. SMN is Delta7 (SMNΔ7;SMN2;Smn-) on a FVB background.

2017-12-12 | GSE81245 | 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

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

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Project description:Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder that affects the spinal motor neurons and leads to progressive muscle wasting and atrophy. It is caused by a reduction in SMN protein levels due to the mutations in the survival motor neuron 1 (SMN1) gene. Human are unique as they possess a homologous pseudogene known as survival motor neuron 2 (SMN2) gene. MicroRNAs (miRNAs) play a role in either translational repression or mRNA degradation. It has been highlighted that dysregulation of miRNA has been a common feature of motor neuron disease such as SMA. Moreover, it is speculated that the dysregulation of miRNAs expression contributes to the pathophysiology of SMA and the vulnerability of SMN protein can be altered by the modulation of specific miRNA. However, there are still lacking of studies on the dysregulation of miRNAs in human SMA patients using iPSC cell models and how the miRNAs correlate with the SMN protein. Hence, we utilized miRNA microarray to identify the miRNAs dysregulated in SMA patients as compared to normal controls in both fibroblast and its derivative induced pluripotent stem cells (iPSCs). Human fibroblasts and iPSCs were cultured and their respective RNA were extracted.

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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

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

Expression data from SMA fibroblasts treated with amiloride or EIPA

Project description:Spinal muscular atrophy (SMA) is an autosomal recessive, pediatric-onset disorder caused by the loss of spinal motor neurons thereby leading to generalized muscle atrophy. SMA is caused by the loss of or mutations in the survival motor neuron 1 (SMN1) gene. SMN1 is duplicated only in human to give rise to the paralogous SMN2 gene. These paralogs are nearly identical except for a cytosine to thymine (C-to-T) transition within an exonic splicing enhancer (ESE) element within exon 7. As a result, the majority of SMN2 transcripts lack exon 7 (SMNΔ7) which produces a truncated and unstable SMN protein. Since SMN2 copy number is inversely related to disease severity, it is a well-established target for SMA therapeutics development. 5-(N-ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of sodium/proton exchangers (NHEs), has previously been shown to increase exon 7 inclusion and SMN protein levels in SMA cells. In this study several different types of NHE inhibitors were evaluated for their ability to modulate SMN2 expression. EIPA as well as 5-(N,N-hexamethylene)amiloride (HMA) increase exon 7 inclusion in SMN2 splicing reporter lines as well as in SMA fibroblasts. The EIPA-induced exon 7 inclusion occurs via a mechanism unique from that used by RG7800, another SMN2 splicing modulator, and does not involve previously identified splicing factors. Transcriptome analysis identified novel targets, including TIA1 and FABP3, for further characterization. EIPA and HMA are more selective at inhibiting the NHE5 isoform, which is expressed in fibroblasts as well as in neuronal cells. These results show that NHE5 inhibition increases SMN2 expression and may be a novel target for therapeutics development.

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The small-molecule flunarizine in spinal muscular atrophy patient fibroblasts impacts on the Gemin components of the SMN complex and RNA-binding proteins relevant to motor neuron diseases

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.

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Liver Steatosis and Mitochondrial Dysfunction in Spinal Muscular Atrophy is Survival Motor Neuron-Dependent and Hepatocyte-Intrinsic

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

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