A gene expression phenotype in lymphocytes from Friedreich ataxia patients
| Autor: | Massimo Pandolfo, David A. Lynch, Susan Perlman, Fuying Gao, Alessandro Filla, Giovanni Coppola, Joel M. Gottesfeld, Heather L. Plasterer, Myriam Rai, Ryan Burnett, James R. Rusche, Daniel H. Geschwind, Francesco Saccà, Revital Versano |
|---|---|
| Přispěvatelé: | Coppola, G, Burnett, R, Perlman, S, Versano, R, Gao, F, Plasterer, H, Rai, M, Sacca', Francesco, Filla, Alessandro, Lynch, Dr, Rusche, Jr, Gottesfeld, Jm, Pandolfo, M, Geschwind, Dh |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Ataxia Cell Culture Techniques Gene Expression Real-Time Polymerase Chain Reaction Peripheral blood mononuclear cell Article 03 medical and health sciences 0302 clinical medicine Iron-Binding Proteins Gene expression medicine Humans Gene 030304 developmental biology 0303 health sciences biology Phenotype Molecular biology 3. Good health Real-time polymerase chain reaction Neurology Friedreich Ataxia Leukocytes Mononuclear Cancer research Frataxin biology.protein Biomarker (medicine) Female Neurology (clinical) medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Annals of Neurology; Vol 70 |
| Popis: | Objective: 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 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 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. Methods: 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 polymerase chain reaction and additional microarrays were used to confirm a core set of genes in multiple independent series. Results: 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 (histone deacetylase inhibitors) on this putative biomarker set, and found that this biochemical phenotype was ameliorated in accordance with drug efficacy. Interpretation: Frataxin downregulation is associated with robust changes in gene expression in PBMCs, providing pathogenetic insights and a core subset of genes that, if verified in vivo, could be used as a peripheral biomarker. ANN NEUROL 2011;70:790–804 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|