Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

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

Haugen, AC and Di Prospero, NA and Parker, JS and Fannin, RD and Chou, J and Meyer, JN and Halweg, C and Collins, JB and Durr, A and Fischbeck, K and Van Houten, B (2010) Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients: Cellular model of pathology. PLoS Genetics, 6 (1). ISSN 1553-7390

[img]
Preview
PDF
Published Version
Available under License : See the attached license file.

Download (755kB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.

Download (1kB)

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.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Haugen, AC
Di Prospero, NA
Parker, JS
Fannin, RD
Chou, J
Meyer, JN
Halweg, C
Collins, JB
Durr, A
Fischbeck, K
Van Houten, Bbev15@pitt.eduBEV15
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorPearson, Christopher E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, Offices, or Units > Hillman Cancer Center
Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute
Date: 1 January 2010
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 6
Number: 1
DOI or Unique Handle: 10.1371/journal.pgen.1000812
Refereed: Yes
ISSN: 1553-7390
MeSH Headings: Adolescent; Adult; Cells, Cultured; Child; Cohort Studies; DNA Damage; Female; Friedreich Ataxia--genetics; Friedreich Ataxia--pathology; Gene Expression; Humans; Iron-Binding Proteins--genetics; Male; Middle Aged; RNA--blood; RNA--genetics; Young Adult
Other ID: NLM PMC2799513
PubMed Central ID: PMC2799513
PubMed ID: 20090835
Date Deposited: 31 Jul 2012 20:50
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/13305

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com


Actions (login required)

View Item View Item