Identification of telomere dysfunction in Friedreich ataxia.

Sara Anjomani Virmouni,Sahar Al-Mahdawi,Chiranjeevi Sandi,Hemad Yasaei,Mark A Pook,Paola Giunti,Predrag Slijepcevic

doi:10.1186/s13024-015-0019-6

Sara Anjomani Virmouni, Sahar Al-Mahdawi + Show 5 more

Open Access

https://doi.org/10.1186/s13024-015-0019-6

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Abstract

BackgroundFriedreich 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.ResultsHere 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.ConclusionsOur finding of dysfunctional telomeres in FRDA cells provides further insight into FRDA molecular disease mechanisms, which may have implications for future FRDA therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0019-6) contains supplementary material, which is available to authorized users.

Highlights

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
The results revealed that the mouse FRDA cell lines, YG8R and YG22R, have significantly increased telomeric repeat fluorescence (P < 0.001) compared to the controls, Y47R and B6 (Fig. 1a)
Overall, the results presented in this study demonstrate a telomere dysfunction phenotype and accelerated telomere shortening in FRDA fibroblasts, together with comparatively reduced telomere lengths in both FRDA leukocytes and cerebellar tissues

Summary

Introduction

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. Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by GAA repeat expansion mutation within intron 1 of the FXN gene. This leads to reduced frataxin expression, defective iron-sulphur cluster (ISC) formation, mitochondrial iron accumulation and oxidative stress, with eventual neuronal cell death. Previous studies have reported FRDA fibroblasts to be more sensitive to ionising radiation than control cells, suggesting that FRDA may be a DNA damage response-deficient disorder [1] This is supported by gene expression studies of human peripheral blood leukocytes that have indicated involvement of DNA repair pathways in FRDA [2, 3]. We aimed to further investigate telomere maintenance in FRDA cells

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