Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients: cellular model of pathology.
Abstract
The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively
inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron
of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial
protein involved in iron homeostasis, is impaired, resulting in a significant reduction
in mRNA and protein levels. Global gene expression analysis was performed in peripheral
blood samples from FRDA patients as compared to controls, which suggested altered
expression patterns pertaining to genotoxic stress. We then confirmed the presence
of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered
an increase in both mitochondrial and nuclear DNA damage in the blood of these patients
(p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of
onset of disease and displayed unique sets of gene alterations involved in immune
response, oxidative phosphorylation, and protein synthesis. Many of the key pathways
observed by transcription profiling were downregulated, and we believe these data
suggest that patients with prolonged frataxin deficiency undergo a systemic survival
response to chronic genotoxic stress and consequent DNA damage detectable in blood.
In conclusion, our results yield insight into the nature and progression of FRDA,
as well as possible therapeutic approaches. Furthermore, the identification of potential
biomarkers, including the DNA damage found in peripheral blood, may have predictive
value in future clinical trials.
Type
Journal articleSubject
AdolescentAdult
Cells, Cultured
Child
Cohort Studies
DNA Damage
Female
Friedreich Ataxia
Gene Expression
Humans
Iron-Binding Proteins
Male
Middle Aged
RNA
Young Adult
Permalink
https://hdl.handle.net/10161/4460Published Version (Please cite this version)
10.1371/journal.pgen.1000812Publication Info
Haugen, Astrid C; Di Prospero, Nicholas A; Parker, Joel S; Fannin, Rick D; Chou, Jeff;
Meyer, Joel N; ... Van Houten, Bennett (2010). Altered gene expression and DNA damage in peripheral blood cells from Friedreich's
ataxia patients: cellular model of pathology. PLoS Genet, 6(1). pp. e1000812. 10.1371/journal.pgen.1000812. Retrieved from https://hdl.handle.net/10161/4460.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
Collections
More Info
Show full item recordScholars@Duke
Joel Meyer
Associate Professor of Environmental Genomics in the Division of Environmental Sciences
and Policy
Dr. Meyer studies the effects of toxic agents and stressors on human and wildlife
health. He is particularly interested in understanding the mechanisms by which environmental
agents cause DNA damage, the molecular processes that organisms employ to protect
prevent and repair DNA damage, and genetic differences that may lead to increased
or decreased sensitivity to DNA damage. Mitochondrial DNA damage and repair, as well
as mitochondrial function in general, are a particular focus. He studies

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info