RNA-Seq results of a neuronal cell model of SBMA, AR-97Q cells, compared to AR-24Q cells
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PROVIDER: PRJNA1061129 | ENA |
REPOSITORIES: ENA
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Project description:RNA-Seq results of oligodendrocyte model of SBMA, AR-97Q cells, compared to AR-17Q cells
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Project description:Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor (AR). Transcriptional changes were compared between a muscle cell model of SBMA (AR-97Q cells) and a control model (AR-24Q cells). RNA-seq gene expression analysis revealed that differentially expressed genes were associated with upregulation of transforming growth factor β (TGFβ) signaling, mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF) signaling, calcium signaling, and NFκB signaling.
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Project description:Transcriptional changes of AR-97Q cells and AR-17Q cells were compared. RNA-seq gene expression analysis revealed that differentially expressed genes were associated with regulation of signaling and regulation of cell communication as biological process, and membrane was most relevant to the genes as cellular component.
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Project description:Purpose: The goal of this study is to evaluate the rescue of SBMA phenotype upon modulation of AR co-factors expression Results: NGS analysis of the transcriptome of quadriceps isolated from SBMA mice upon treatment reveal the rescue (partial or total) of assemblies of genes involved in SBMA pathogenesis Conclusion: targeting overexpressed AR co-regulators is a new therapeutic approach for SBMA to attenuate the toxic GOF without exacerbating AR LOF
2022-11-04 | GSE193539 | GEO
Project description:Emerging evidence implicates transcriptional dyseregulation within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disorder. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q KI), a polyQ AR transgenic model (AR97Q Tg), and a transgenic mouse which overexpresses wild type AR solely in muscle (HSA-AR Tg). We performed microarray analysis of lower hindlimb muscles taken from these three models using high density oligonucleotide arrays. Changes in gene expression relative to wild type controls were evaluated separately in each strain. We validated our results using quantitative RT-PCR. Patterns of gene expression that are common to all lines and unique to each are described. When considered globally, the degree of overlap between the three models is approximately equivalent, and several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, Huntingtonâ??s disease, muscle atrophy and myogenesis. By comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA. Keywords: Gene expression in transgenic mice and disease state analysis We used microarray (38.5K oligo mouse array, which contain 35,302 of 70mer oligonucleotide probes largely derived from constitutively expressed exons and 3,482 of controls) to analyze gene expression in limb muscles of transgenic mice. Three mouse models of KD/SBMA were used: HSA-AR, AR113Q knock-in and AR97Q. HSA-AR transgenic male mice (n=5) and their WT brothers (n=8, all mice were 110-130 days of age) were used in this experiment. ARQ113-Knock In males (n=3, 3-4 months of age), and transgenic AR97Q males and WT brothers (n= 6 of each) were used in this study. For both HSA-AR and AR113Q samples, the log2 ratio of experimental samples (Cy5) and reference RNA(Cy3) was obtained, and log2 ratios from mutant samples were then subtracted from log2 ratios from WT controls. AR97Q males (Cy5) were simply compared with their WT brothers (Cy3) using a log2 ratio, rather than being first compared with reference RNA.
2010-10-12 | E-GEOD-10190 | biostudies-arrayexpress
Project description:Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor (AR). Previous studies have shown that transcriptional dysregulation and mitochondrial impairment occur in SBMA. We used gene-expression analysis and ChIP-sequencing to map transcriptional changes in SBMA induced pluripotent stem cell-derived motor neurons. The SBMA cells had decreased expression of genes encoding electron transport chain subunits and other metabolic proteins, associated with reduced histone acetylation which may be contributing to mitochondrial dysfunction. AR ChIP-sequencing results indicate that this is not a direct transcriptional effect of mutant AR on mitochondrial gene expression. Furthermore, we found decreased acetyl-CoA, and pyruvate supplementation to correct this deficiency improved mitochondrial function and SBMA motor neuron viability. We propose that epigenetic dysregulation of metabolic genes contributes to reduced mitochondrial ATP production. Our results show a molecular link between altered epigenetic regulation and mitochondrial metabolism that contributes to neurodegeneration.
2020-08-10 | GSE140017 | GEO
Project description:Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing neuromuscular disease caused by a polyglutamine (polyQ)-encoding CAG repeat expansion in the androgen receptor (AR) gene, leading to AR aggregation, lower motor neuron death, and muscle atrophy. AR is a ligand-activated transcription factor that regulates neuronal architecture and promotes axon regeneration; however, whether AR transcriptional functions contribute to disease pathogenesis is not fully understood. Using a differentiated PC12 cell model of SBMA, we identified dysfunction of polyQ-expanded AR in its regulation of neurite growth and maintenance. Specifically, we found that in the presence of androgens, polyQ-expanded AR inhibited neurite outgrowth, induced neurite retraction, and inhibited neurite regrowth. This dysfunction was independent of polyQ-expanded AR transcriptional activity at androgen response elements (AREs). We further showed that the formation of polyQ-expanded AR intranuclear inclusions promoted neurite retraction, which coincided with reduced expression of the neuronal differentiation marker -III-Tubulin. Finally, we revealed that cell death is not the primary outcome for cells undergoing neurite retraction; rather, these cells become senescent. Our findings reveal that mechanisms independent of AR canonical transcriptional activity underly neurite defects in a cell model of SBMA and identify senescence as a previously unappreciated pathway implicated in this pathology. These findings suggest that, in the absence of a role for AR canonical transcriptional activity in the SBMA pathologies described here, the development of SBMA therapeutics that preserve this activity may be desirable. This approach may be broadly applicable to other polyglutamine diseases such as Huntington’s disease and spinocerebellar ataxias.
2024-07-05 | GSE267802 | GEO
Project description:Expansion of a polyglutamine (polyQ) tract in the gene for the androgen receptor (AR) results in partial loss of transactivation function and causes spinobulbar muscular atrophy (SBMA). Modification of AR by small ubiquitin-like modifier (SUMO) reduces AR function in a promoter context-dependent manner. We used microarrays to confirm and demonstrate loss of AR function from polyQ expansion and to test the degree to which AR function is altered by preventing polyQ AR SUMOylation. PC12 cells expressing AR10Q, AR112Q, or nonSUMOylatable AR112Q (KRKR) in the presence or absence of synthetic androgen R1881 were assessed for alterations in AR function by comparing gene expression changes with each AR variant in response to ligand.
2014-08-23 | E-GEOD-50383 | biostudies-arrayexpress
Project description:To identify the gene expression changes that are specific to SBMA, we prepared total mRNA samples from the spinal cords of transgenic mice carrying a full-length human AR with 97 CAGs (AR-97Q), transgenic mice bearing a wild-type allele of AR with 24 CAGs (AR-24Q), and the wild-type littermates of the AR-97Q mice (C57BL/6). We used AR-97Q (Line #7-8) male mice because they show progressive muscular atrophy and weakness as well as SBMA-like pathology such as the accumulation of the pathogenic androgen receptor in the nucleus of motor neurons. Using microarray analysis, we identified the genes with significantly altered expression among the three types of mice.
2012-08-04 | GSE39865 | GEO
Project description:To identify the gene expression changes that are specific to SBMA, we prepared total mRNA samples from the spinal cords of transgenic mice carrying a full-length human AR with 97 CAGs (AR-97Q), transgenic mice bearing a wild-type allele of AR with 24 CAGs (AR-24Q), and the wild-type littermates of the AR-97Q mice (C57BL/6). We used AR-97Q (Line #7-8) male mice because they show progressive muscular atrophy and weakness as well as SBMA-like pathology such as the accumulation of the pathogenic androgen receptor in the nucleus of motor neurons. Using microarray analysis, we identified the genes with significantly altered expression among the three types of mice. For each group, we examined the male mice at 7-9, 10-12, and 13-15 weeks of age. These stages were chosen because the AR-97Q mice are generally asymptomatic at 7-9 weeks of age (before-onset stage), present with mild motor impairment at 10-12 weeks (early stage), and are severely weakened with profound muscle atrophy at 13-15 weeks (advanced stage). RNA from the total spinal cord, excluding the dorsal root ganglia, was isolated from three mice of each genotype at each stage. For wild-type, pooled sample for three mice were used in each stage.
2012-08-03 | E-GEOD-39865 | biostudies-arrayexpress