Identification of telomere dysfunction in Friedreich ataxia.

Abstract

BACKGROUND:

Friedreich ataxia (FRDA) is a progressive inherited neurodegenerative disorder caused by mutation of the FXN gene, resulting in decreased frataxin expression, mitochondrial dysfunction and oxidative stress. A recent study has identified shorter telomeres in FRDA patient leukocytes as a possible disease biomarker.

RESULTS:

Here we aimed to investigate both telomere structure and function in FRDA cells. Our results confirmed telomere shortening in FRDA patient leukocytes and identified similar telomere shortening in FRDA patient autopsy cerebellar tissues. However, FRDA fibroblasts showed significantly longer telomeres at early passage, occurring in the absence of telomerase activity, but with activation of an alternative lengthening of telomeres (ALT)-like mechanism. These cells also showed accelerated telomere shortening as population doubling increases. Furthermore, telomere dysfunction-induced foci (TIF) analysis revealed that FRDA fibroblasts have dysfunctional telomeres.

CONCLUSIONS:

Our finding of dysfunctional telomeres in FRDA cells provides further insight into FRDA molecular disease mechanisms, which may have implications for future FRDA therapy.

• Authors: Sara Anjomani Virmouni, Sahar Al-Mahdawi, Chiranjeevi Sandi, Hemad Yasaei, Paola Giunti, Predrag Slijepcevic, Mark A Pook
• Journal: Molecular neurodegeneration (Mol Neurodegener) Vol. 10 Pg. 22 (Jun 10 2015) ISSN: 1750-1326 [Electronic] England
• PMID: 26059974 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Telomerase

Topics

• Adolescent
• Adult
• Animals
• Cell Division
• Cells, Cultured
• Cerebellum (ultrastructure)
• DNA Damage
• DNA Repair
• Female
• Fibroblasts (ultrastructure)
• Friedreich Ataxia (genetics, pathology)
• Humans
• In Situ Hybridization, Fluorescence
• Leukocytes (ultrastructure)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Oxidative Stress
• Recombination, Genetic
• Telomerase (metabolism)
• Telomere (genetics, ultrastructure)
• Telomere Homeostasis (physiology)
• Telomere Shortening (genetics)
• Young Adult