Identification of telomere dysfunction in Friedreich ataxia

Molecular Neurodegeneration

Mark A. Pook³  Predrag Slijepcevic⁴  Paola Giunti¹  Hemad Yasaei⁴  Chiranjeevi Sandi²  Sahar Al-Mahdawi³  Sara Anjomani Virmouni³ 

[1] Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK;Current address: Uro-Oncology Research Group, Cancer Research UK-Cambridge Institute, University of Cambridge, Cambridge, UK;Synthetic Biology Theme, Institute of Environment, Health & Societies, Brunel University London, Uxbridge, UK;Division of Biosciences, Department of Life Sciences, College of Health & Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK

关键词: Telomere dysfunction;    ALT;    Alternative lengthening of telomeres;    Mouse model;    GAA repeat expansion;    FXN;    frataxin;    FRDA;    Friedreich ataxia;   

Others  :  1211843
DOI  :  10.1186/s13024-015-0019-6

 received in 2014-10-31, accepted in 2015-05-26,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Anjomani Virmouni et al.

【 图 表 】

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