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Gene Expression Analysis of laser-microdissected motorneurons in Spinal Muscular Atrophy (SMA)

ABSTRACT: Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease and is the second most common genetic disorder leading to death in childhood. Stem cell transplantation could represent a therapeutic approach for motor neuron diseases such as SMA. We examined the theraputics effects of a spinal cord neural stem cell population and their ability to modify SMA phenotype. Microarray technology was used to assess the global gene expression profile of laser-microdissected motoneurons obtained by transplanted and veichle treated SMA, and wildtype mice. Keywords: Comparative Gene Expression Analysis

ORGANISM(S): Mus musculus

PROVIDER: GSE10224 | GEO | 2008/08/06

SECONDARY ACCESSION(S): PRJNA108289

REPOSITORIES: GEO

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Transcription profiling of mouse laser-microdissected motorneurons in a Spinal Muscular Atrophy model (SMA)

Project description:Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease and is the second most common genetic disorder leading to death in childhood. Stem cell transplantation could represent a therapeutic approach for motor neuron diseases such as SMA. We examined the theraputics effects of a spinal cord neural stem cell population and their ability to modify SMA phenotype. Microarray technology was used to assess the global gene expression profile of laser-microdissected motoneurons obtained by transplanted and veichle treated SMA, and wildtype mice. Experiment Overall Design: The microarray data derived from three different groups: wildtype controls (vehicle treated), transgenic SMA (vehicle treated) and transplanted SMA mice. Each population consists of three RNA profiling samples.

2008-10-20 | E-GEOD-10224 | biostudies-arrayexpress

Gene Expression Analysis of spinal cord obtained from a mouse model of severe Spinal Muscular Atrophy (SMA)

Project description:Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease and is the second most common genetic disorder leading to death in childhood. No effective therapy is currently available. It has been suggested that M-NM-2-lactam antibiotics such as ceftriaxone may offer neuroprotection in motoneuron disease. We investigated the therapeutic effect of ceftriaxone in a murine model of SMA. Microarray technology was used to assess the global gene expression profile of spinal cord obtained by ceftriaxone-treated and vehicle treated SMA mice. Comparative Gene Expression Analysis. The microarray data derived from three different groups: wildtype controls, transgenic SMA (vehicle treated) and ceftriaxone-treated SMA mice. Each population consists of four RNA profiling samples.

2013-12-01 | E-GEOD-19674 | biostudies-arrayexpress

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2013-12-01 | GSE19674 | 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

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Project description:Motor neurons are selectively vulnerable in spinal muscular atrophy (SMA). However, some brainstem motor neuron groups, including oculomotor and trochlear, which innervate the muscles around the eyes, are for unknown reasons spared. Here, we investigate the transcriptional dynamics in discrete neuronal populations in health and SMA to identify mechanisms of vulnerability and resistance. Such mechanisms could reveal targets for future gene therapy studies aimed towards preserving vulnerable motor neurons.

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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

Mitochondrial defects contribute to impaired translational in SMA motor neurons

Project description:Spinal muscular atrophy (SMA) is a neuromuscular disease, characterized by loss of lower alpha motoneurons, which leads to proximal muscle weakness. SMA is caused by reduced levels of Survival of Motor Neuron protein due to biallelic deletions or mutations in the SMN1 gene. Dysfunctional mitochondria can harm cells by decreased ATP production, but also by increased oxidative stress due to elevated production of reactive oxygen species (ROS). In this study, whole proteome analysis was performed using the Taiwanese SMA mouse model on an FVB/N background to identify changes in the proteome related to oxidative stress. Therefore, primary WT and SMA motoneurons were treated with a known anti-oxidant N-Acetylcysteine, the ROS inducer menadione and the cell culture supplement sodium pyruvate. Furthermore, this study aims to investigate changes in mRNA translation initiation affected by oxidative stress in SMA.

2020-12-23 | PXD020403 | Pride

Selective Death in Spinal Muscular Atrophy: Genome-Wide RNA-Seq Using Purified Patient-Derived Motor Neurons

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

Global gene expression profile and splicing events of iPS-derived motorneurons from SMA patient, unaffected father and TGC-treated cells

Project description:Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease and is the second most common genetic disorder leading to death in childhood. Motoneurons derived from induced pluripotent stem cells (iPSC) obtained by reprogramming SMA patient and his healthy father fibroblasts, and genetically corrected SMA-iPSC obtained converting SMN2 into SMN1 with target gene correction (TGC), were used to study gene expression and splicing events linked to pathogenetic mechanisms. Microarray technology was used to assess the global gene expression profile as well as splicing events of iPS-derived motorneurons from SMA patient, unaffected father and TGC-treated cells. The microarray data derived from three different groups: SMA patient, healty father and treated SMA patient's cells. Each population consists of three RNA profiling cell samples.

2013-01-04 | E-GEOD-27205 | biostudies-arrayexpress

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