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A Gene Expression Phenotype In Lymphocytes From Friedreich’s Ataxia Patients

ABSTRACT: Gene expression studies in peripheral tissues from patients with neurodegenerative disorders can provide insights into disease pathogenesis, and identify potential biomarkers, an important goal of translational research in neurodegeneration. Friedreich’s Ataxia (FRDA) is a chronic neurodegenerative disease caused by reduced transcription of frataxin, a ubiquitously expressed protein. We studied in vitro lymphocytes from FRDA patients and carriers, in order to identify a peripheral gene expression phenotype. Peripheral biomarkers related to disease status would be extremely valuable for assessing drug efficacy and could provide new pathophysiological insights. We identified a subset of genes changed in cells from patients with pathological frataxin deficiency and a core set of these genes were confirmed in independent series. Changes in gene expression were related to the mitochondria, lipid metabolism, cell cycle, and DNA repair, consistent with FRDA’s known pathophysiology. We evaluated the in vitro effect of multiple compounds (HDAC inhibitors) on this putative biomarker set, and found that this biochemical phenotype was ameliorated in accordance with drug efficacy. Frataxin downregulation is associated with robust changes in gene expression in PBMCs, providing pathogenetic insights and a core subset of genes which, if verified in vivo, could be used as a peripheral biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE30933 | GEO | 2011/07/26

SECONDARY ACCESSION(S): PRJNA146285

REPOSITORIES: GEO

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A Gene Expression Phenotype In Lymphocytes From Friedreich’s Ataxia Patients

Project description:Gene expression studies in peripheral tissues from patients with neurodegenerative disorders can provide insights into disease pathogenesis, and identify potential biomarkers, an important goal of translational research in neurodegeneration. Friedreich’s Ataxia (FRDA) is a chronic neurodegenerative disease caused by reduced transcription of frataxin, a ubiquitously expressed protein. We studied in vitro lymphocytes from FRDA patients and carriers, in order to identify a peripheral gene expression phenotype. Peripheral biomarkers related to disease status would be extremely valuable for assessing drug efficacy and could provide new pathophysiological insights. We identified a subset of genes changed in cells from patients with pathological frataxin deficiency and a core set of these genes were confirmed in independent series. Changes in gene expression were related to the mitochondria, lipid metabolism, cell cycle, and DNA repair, consistent with FRDA’s known pathophysiology. We evaluated the in vitro effect of multiple compounds (HDAC inhibitors) on this putative biomarker set, and found that this biochemical phenotype was ameliorated in accordance with drug efficacy. Frataxin downregulation is associated with robust changes in gene expression in PBMCs, providing pathogenetic insights and a core subset of genes which, if verified in vivo, could be used as a peripheral biomarker. We characterized the gene expression profiles in peripheral blood mononuclear cells (PBMCs) from FRDA patients, compared with controls and related carriers. Cells were studied both before and after in vitro treatment with compounds that increase frataxin levels. Quantitative real-time PCR and additional microarrays were used to confirm a core set of genes in multiple independent series

2011-07-25 | E-GEOD-30933 | biostudies-arrayexpress

Comprehensive Analysis of Gene Expression Patterns in Friedreich’s Ataxia Fibroblasts by RNA Sequencing Reveals Altered Levels of Protein Synthesis Factors and Solute Carriers

Project description:Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disease usually caused by large homozygous expansions of GAA repeat sequences in intron 1 of the frataxin (FXN) gene. FRDA patients have low FXN mRNA and frataxin protein levels when compared with heterozygous carriers or healthy controls. Presently, there is no effective treatment for FRDA, and biomarkers to measure therapeutic trial outcomes and/or to gauge disease progression are lacking. Peripheral tissues, including blood cells, buccal cells, and skin fibroblasts, can readily be isolated from FRDA patients and used to define molecular hallmarks of disease pathogenesis. However, because these tissues are not directly involved in disease pathogenesis, their relevance as models of the molecular aspects of the disease is yet to be decided. Transcriptome profiling of FRDA skin fibroblasts revealed significantly upregulated expression of genes encoding plasma membrane solute carrier proteins. Conversely, the expression of genes encoding accessory factors and enzymes involved in cytoplasmic and mitochondrial protein synthesis was consistently decreased in the FRDA cells. Finally, comparison of genes differentially expressed in FRDA fibroblasts to 3 previously published gene expression signatures defined for FRDA blood cells showed substantial overlap between the independent datasets, including correspondingly deficient expression of antioxidant defense genes. Together, these results indicate that gene expression profiling of cells derived from peripheral tissues can, in fact, consistently reveal novel molecular pathways of the disease.

2017-09-27 | GSE104288 | GEO

Friedreich’s Ataxia Induced Pluripotent Stem Cells Recapitulate GAA•TTC Triplet-Repeat Instability

Project description:The inherited neurodegenerative disease Friedreich’s ataxia (FRDA) is caused by hyperexpansion of GAA•TTC trinucleotide repeats within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAA•TTC repeats causes heterochromatin-mediated silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts through retroviral transduction of transcription factors. FXN gene repression is maintained in the iPSCs, as are the mRNA and miRNA global expression signatures reflecting the human disease. GAA•TTC repeats uniquely in FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme Msh2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in the iPSCs, occupies FXN intron 1, and shRNA silencing of Msh2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA.

2010-07-02 | GSE22651 | GEO

Epigenetic therapy for Friedreich ataxia.

Project description:We set out to investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients. In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered. We used a human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, to determine the efficacy of a 2-aminobenzamide HDACi (109) as a modulator of FXN gene expression and chromatin histone modifications. FRDA patients were dosed in 4 cohorts, ranging from 30mg/day to 240mg/day of the formulated drug product of HDACi 109, RG2833. Patients were monitored for adverse effects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood cells. Gene expression profiles were obtained using the Illumina HT12v4 Gene Expression BeadArray.

2015-01-29 | E-GEOD-65399 | biostudies-arrayexpress

Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients

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

Peripheral blood biomarkers in Friedreich's ataxia

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

Epigenetic therapy for Friedreich ataxia.

2015-01-29 | GSE65399 | GEO

Small RNA-seq analysis of circulating miRNAs to identify phenotypic variability in Friedreich's ataxia patients

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

Lipidomics analysis of Friedreich's ataxia (FRDA) (part II)

Project description:Friedreich’s Ataxia (FRDA) is an autosomal neurodegenerative disease caused by the deficiency of protein frataxin. Frataxin functions in the assembly of iron-sulfur clusters that are important for iron homeostasis and metabolic functions. To identify metabolic features that can be used for potential biomarkers in FRDA plasma, we performed a targeted multi-omics (metabolomics, lipidomics, and proteomics) analysis using discovery-validation cohort design. Muti-omics analysis revealed that FRDA patients had dysregulated sphingolipid metabolism, phospholipid metabolism, citric acid cycle, amino acid metabolism, and apolipoprotein metabolism. Sphingolipid dysfunctions were revealed by decreased very long chain ceramides but unchanged long chain ceramides in FRDA plasma, which resulted in the increased ratio of long chain ceramides to very long chain ceramides. Decreased very long chain ceramides distinguished FRDA patients from healthy controls and showed good predictive capacities with AUC values from 0.75 to 0.85. Furthermore, by performing lipidomic and stable isotope tracing experiment in induced pluripotent stem cell differentiated cardiomyocytes (iPSC-CMs, we demonstrated that frataxin deficiency affected ceramide synthase (CerS2), and preferentially enriched long chain ceramides and depleted very long chain ceramides. Moreover, ceramide metabolism was differentially regulated in a tissue-specific manner. Finally, machine learning model increased the prediction of FRDA using the combination of three metabolites (AUC > 0.9). In conclusion, decreased very long chain ceramides are potential biomarkers and therapeutic target in FRDA patients.

2022-07-29 | ST002243 | MetabolomicsWorkbench

Metabolomics analysis of Friedreich's ataxia (FRDA) (part I)

2022-07-29 | ST002244 | MetabolomicsWorkbench

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