Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients: cellular model of pathology.

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Date

2010-01-15

Authors

Haugen, Astrid C
Di Prospero, Nicholas A
Parker, Joel S
Fannin, Rick D
Chou, Jeff
Meyer, Joel N
Halweg, Christopher
Collins, Jennifer B
Durr, Alexandra
Fischbeck, Kenneth

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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.

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Adolescent, Adult, Cells, Cultured, Child, Cohort Studies, DNA Damage, Female, Friedreich Ataxia, Gene Expression, Humans, Iron-Binding Proteins, Male, Middle Aged, RNA, Young Adult

Citation

Published Version (Please cite this version)

10.1371/journal.pgen.1000812

Publication Info

Haugen, Astrid C, Nicholas A Di Prospero, Joel S Parker, Rick D Fannin, Jeff Chou, Joel N Meyer, Christopher Halweg, Jennifer B Collins, et al. (2010). Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients: cellular model of pathology. PLoS Genet, 6(1). p. e1000812. 10.1371/journal.pgen.1000812 Retrieved from https://hdl.handle.net/10161/4460.

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Scholars@Duke

Meyer

Joel Meyer

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 these effects in the nematode Caenorhabditis elegans, in cell culture, and collaboratively in other laboratory model organisms as well as in human populations in the USA and globally.


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