Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE11204 | GEO | 2009/12/08
SECONDARY ACCESSION(S): PRJNA106805
REPOSITORIES: GEO
Similar Datasets
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: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: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; 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: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.
2009-06-02 | GSE15848 | 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.
2009-06-02 | GSE15843 | 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.
2017-10-18 | GSE105052 | GEO
Project description:Friedreich´s Ataxia (FRDA) is a severe neuromuscular disorder caused by a deficiency of the mitochondrial protein frataxin. While some aspects of FRDA pathology are developmental, the causes underlying the steady progression are unclear. The inaccessibility of key affected tissues to sampling is a main hurdle. Skeletal muscle displays a disease phenotype and may be sampled in vivo to address open questions on FRDA pathophysiology. We performed a mass spectrometry (MS)-based proteomics analysis in gastrocnemius skeletal muscle biopsies from genetically confirmed FRDA patients (n=5) and controls. Our data corroborate a predominant mitochondrial biosignature of FRDA, which extends beyond a mere oxidative phosphorylation failure. Skeletal muscle proteomics highlighted a derangement of mitochondrial architecture and maintenance pathways and an adaptative metabolic shift of contractile proteins. The present findings are relevant for the design of future therapeutic strategies and highlight the value of skeletal muscle -omics as disease state readout in FRDA.
2023-12-04 | PXD044554 | Pride
Project description:RNA sequencing of skeletal muscle biopsies from healthy controls and Friedreich's Ataxia (FRDA) patients before and after treatment with recombinant human erythropoietin (rhuEPO) to dissect the mechanisms of disease.
2023-04-01 | GSE226646 | 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