Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's Ataxia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE226646 | GEO | 2023/04/01
REPOSITORIES: GEO
Similar Datasets
Project description:Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's Ataxia
| PRJNA940990 | ENA
Project description:Frataxin, a conserved mitochondrial protein involved in iron homeostasis, is reduced in patients with Friedreich’s ataxia (FRDA). Transcription profiling and DNA damage assays were performed on blood cells from FRDA patients. Altered expression patterns pertained to immune response, signaling pathways, transcription, apoptosis, and genotoxic stress response pathways. FRDA patients had significantly more mitochondrial and nuclear DNA damage than a control population. Frataxin mRNA levels correlated with age of onset and displayed unique sets of gene alterations involved in oxidative phosphorylation and protein synthesis. Thus analysis of blood in FRDA patients yields insight into the nature and progression of the disease, as well as potential therapeutic approaches. Keywords: Friedreich's ataxia; frataxin; mitochondrial DNA damage; nuclear DNA damage; genotoxic stress
2009-12-08 | GSE11204 | GEO
Project description:Friedreich’s ataxia (FRDA; OMIM 229300), an autosomal recessive neurodegenerative mitochondrial disease, is the most prevalent hereditary ataxia. In addition, FRDA patients showed additional non-neurological features such as scoliosis, diabetes and cardiac complications. Hypertrophic cardiomyopathy, which is found in two thirds of patients at the time of diagnosis, is the primary cause of death in these patients. In this data set, using small RNA-sequencing of small RNA purified from plasma samples of FRDA patients and controls we identified differential expression of miRNAs (hsa-miR-128-3p, hsa-miR-625-3p, hsa-miR-130b-5p, hsa-miR-151a-5p, hsa-miR-330-3p, hsa-miR-323a-3p, and hsa-miR-142-3p) between both groups. In addition, we found that miR-323a-3p can be used as a biomarker for differentiation of FRDA patients with cardiac problems. Identification of miRNA signatures could therefore provide new molecular explanation for pathological mechanisms occurring during the natural history of the FRDA. Since miRNA levels change with disease progression and pharmacological interventions, miRNAs will contribute to design new therapeutic strategies and improve clinical decisions. Plama miRNA profiles of 25 Friedreich's ataxia patients and 17 healthy subjects were generated by deep sequencing using Illumina HiScan SQ.
2017-10-18 | E-GEOD-105052 | biostudies-arrayexpress
Project description:Friedreich's ataxia (FRDA) is an autosomal-recessive neurodegenerative and cardiac disorder which occurs when transcription of the frataxin (FXN) gene is silenced due to the expansion of GAA·TTC repeats in intron 1 of the same gene, leading loss of the essential mitochondrial protein frataxin with several impairment in iron metabolism and respiration, primarily affects the sensory DRG neurons. A major limitation in the study of FRDA is the lack of robust animal and cellular models. To fill this gap, this study presents a novel 3D protocol to generate dorsal root ganglia-like organoids (DRGOs) from human iPSCs in which to model Friedreich's ataxia. DRGOs show a robust expression pattern of peripheral markers, are electro-physiologically active and out-perform peripheral sensory neurons generated with a traditional 2D protocol. Furthermore, when co-cultured with human stretch receptor intrafusal muscle fibers, DRGOs contact their peripheral target and form an in vitro muscle spindle. DRGOs generated from FRDA patient-derived iPSCs recapitulate several aspects of FRDA pathology including reduced expression of FXN and TCA-cycle components and mitochondrial fragmentation. We present also the recovery of this pathological signs, achieved by a new CRISPR-Cas9 mediated deletion of the GAA·TTC tract along with the majority of the affected intron. FRDA patient edited DRGOs with the long deletion boast normalized markers of oxidative stress, as well as recovered mitochondrial defect, particularly in the axonal compartment.
2020-07-27 | GSE133755 | GEO
Project description:The identification of biomarkers for Friedreich’s ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, is an important goal for disease follow-up and assessment of treatments. Clinical scales are not sensitive enough to detect small, short-term changes that may be indicative of treatment effectiveness. We used differential expression, correlation with expansion size, network analysis, machine learning, and enrichment analysis to identify gene expression biomarkers which differentiated FRDA patients from both heterozygous expansion carriers and controls (821 individuals in total), resulting in a disease signature for FRDA. Our 27-gene expression panel includes genes which are linked to inflammation, lipid metabolism and apoptosis, and overlaps with previous studies and a with a novel mouse model for FRDA. Future studies should seek to expand the search for FRDA biomarkers to include changes in epigenetic regulation and protein expression.
2018-07-26 | GSE102008 | GEO
Project description:ObjectiveIn Friedreich's ataxia (FRDA), the most affected tissues are not accessible to sampling and available transcriptomic findings originate from blood-derived cells and animal models. Herein, we aimed at dissecting for the first time the pathophysiology of FRDA by means of RNA-sequencing in an affected tissue sampled in vivo.MethodsSkeletal muscle biopsies were collected from seven FRDA patients before and after treatment with recombinant human Erythropoietin (rhuEPO) within a clinical trial. Total RNA extraction, 3'-mRNA library preparation and sequencing were performed according to standard procedures. We tested for differential gene expression with DESeq2 and performed gene set enrichment analysis with respect to control subjects.ResultsFRDA transcriptomes showed 1873 genes differentially expressed from controls. Two main signatures emerged: (1) a global downregulation of the mitochondrial transcriptome as well as of ribosome/translational machinery and (2) an upregulation of genes related to transcription and chromatin regulation, especially of repressor terms. Downregulation of the mitochondrial transcriptome was more profound than previously shown in other cellular systems. Furthermore, we observed in FRDA patients a marked upregulation of leptin, the master regulator of energy homeostasis. RhuEPO treatment further enhanced leptin expression.InterpretationOur findings reflect a double hit in the pathophysiology of FRDA: a transcriptional/translational issue and a profound mitochondrial failure downstream. Leptin upregulation in the skeletal muscle in FRDA may represent a compensatory mechanism of mitochondrial dysfunction, which is amenable to pharmacological boosting. Skeletal muscle transcriptomics is a valuable biomarker to monitor therapeutic interventions in FRDA.
| S-EPMC10281753 | biostudies-literature
Project description:Friedreich’s ataxia (FRDA; OMIM 229300), an autosomal recessive neurodegenerative mitochondrial disease, is the most prevalent hereditary ataxia. In addition, FRDA patients showed additional non-neurological features such as scoliosis, diabetes and cardiac complications. Hypertrophic cardiomyopathy, which is found in two thirds of patients at the time of diagnosis, is the primary cause of death in these patients. In this data set, using small RNA-sequencing of small RNA purified from plasma samples of FRDA patients and controls we identified differential expression of miRNAs (hsa-miR-128-3p, hsa-miR-625-3p, hsa-miR-130b-5p, hsa-miR-151a-5p, hsa-miR-330-3p, hsa-miR-323a-3p, and hsa-miR-142-3p) between both groups. In addition, we found that miR-323a-3p can be used as a biomarker for differentiation of FRDA patients with cardiac problems. Identification of miRNA signatures could therefore provide new molecular explanation for pathological mechanisms occurring during the natural history of the FRDA. Since miRNA levels change with disease progression and pharmacological interventions, miRNAs will contribute to design new therapeutic strategies and improve clinical decisions.
2017-10-18 | GSE105052 | GEO
Project description:Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich's ataxia Friedreich's ataxia (FRDA), the most common inherited ataxia, is characterized by focal neurodegeneration, diabetes mellitus, and life-threatening cardiomyopathy. Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPARγ coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPARγ pathway affects frataxin levels in vitro, supporting PPARγ as a novel therapeutic target in FRDA. To compare frataxin deficient (KIKO) mice vs. WT, heart, skeletal muscle, and liver.
2010-04-09 | E-GEOD-15848 | biostudies-arrayexpress
Project description:Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich's ataxia Friedreich's ataxia (FRDA), the most common inherited ataxia, is characterized by focal neurodegeneration, diabetes mellitus, and life-threatening cardiomyopathy. Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPARγ coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPARγ pathway affects frataxin levels in vitro, supporting PPARγ as a novel therapeutic target in FRDA. To compare frataxin deficient (KIKO) mice vs. WT, heart and skeletal muscle. Three replicates (KIKO vs WT), with dye swap
2009-06-02 | E-GEOD-15843 | biostudies-arrayexpress
Project description:Friedreich's Ataxia (FRDA), a rare, inherited, progressive degenerative disease, is caused by a defective expression of mitochondrial protein frataxin (FXN), due to homozygous hyper-expansion of GAA triplets in the gene which severely reduce its transcription. FXN is crucial for cell survival and its deficiency in humans critically affects viability of neurons, cardiomyocytes and pancreatic beta cells. Around two thirds of individuals with FRDA show typical manifestation of hypertrophic cardiomyopathy, that can progress in heart failure and death. Except for FXN, very few genes have been correlated with ataxia and cardiac disease in FRDA. To identify other genes involved in pathogenesis of FRDA, a microarray analysis on FRDA patient's lymphoblastoid cells stably reconstituted with FXN was performed. HS-1 associated protein X-1 (HAX-1), a family of proteins playing important roles in the protection of cardiomyocytes from apoptosis, is the highest up-regulated transcript (FC=+2, p<0.0006). HAX-1 is highly expressed in heart and HAX-1 heterozygous-deficient hearts exhibit increases in infarct size. The microarray result was further assessed with qRT-PCR and western blot analysis performed on HEK293 stably transfected with empty vector or FXN-vector and lymphoblasts from FRDA patients compared to clinically unaffected heterozygous parents, confirming a strong co-expression of HAX-1 and FXN both at mRNA and protein level. Moreover, analysis of FXN and HAX-1 in peripheral blood mononuclear cells (PBMCs) of FRDA patients (n=13), heterozygous parents (n=6) and non-correlated healthy controls (n=13) revealed that their expressions are correlated. The positive correlation is more significant in FRDA patients showing a cardiac disease (10/13). The positive correlation between frataxin and HAX-1 expression level suggests a potential link of HAX-1 expression to pro-survival or protective cellular pathways related to frataxin. Thus, HAX-1 may be considered a specific biomarker of cardiomyopathy in FRDA and may represent a prognostic implement in these patients. Moreover, the discovery of novel genetic "risk" or "protective" factors in cardiomyopathy is crucial to improve risk stratification strategies and to identify new therapeutic targets.
2019-12-31 | GSE108200 | GEO