title: A gene expression phenotype in lymphocytes from Friedreich ataxia patients.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Ryan
authors.initials: R
authors.lastname: Burnett
authors.forename: Susan
authors.initials: S
authors.lastname: Perlman
authors.forename: Revital
authors.initials: R
authors.lastname: Versano
authors.forename: Fuying
authors.initials: F
authors.lastname: Gao
authors.forename: Heather
authors.initials: H
authors.lastname: Plasterer
authors.forename: Myriam
authors.initials: M
authors.lastname: Rai
authors.forename: Francesco
authors.initials: F
authors.lastname: Saccá
authors.forename: Alessandro
authors.initials: A
authors.lastname: Filla
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
authors.forename: James R
authors.initials: JR
authors.lastname: Rusche
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D000328:Adult; D018929:Cell Culture Techniques; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D033862:Iron-Binding Proteins / Q000187:drug effects* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D008297:Male; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D000096923:Frataxin