Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2015

Open Access 01-12-2015 | Research article

Identification of telomere dysfunction in Friedreich ataxia

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

Published in: Molecular Neurodegeneration | Issue 1/2015

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Chamberlain S, Lewis PD. Studies of cellular hypersensitivity to ionising radiation in Friedreich’s ataxia. J Neurol Neurosurg Psychiatry. 1982;45:1136–8.PubMedCentralPubMedCrossRef
2.
Haugen AC, Di Prospero NA, Parker JS, Fannin RD, Chou J, Meyer JN, et al. Altered gene expression and DNA damage in peripheral blood cells from Friedreich’s ataxia patients: cellular model of pathology. PLoS Genet. 2010;6:e1000812.PubMedCentralPubMedCrossRef
3.
Coppola G, Burnett R, Perlman S, Versano R, Gao F, Plasterer H, et al. A gene expression phenotype in lymphocytes from Friedreich ataxia patients. Ann Neurol. 2011;70:790–804.PubMedCentralPubMedCrossRef
4.
von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27:339–44.CrossRef
5.
Castaldo I, Vergara P, Pinelli M, Filla A, De Michele G, Cocozza S, et al. Can telomere shortening in human peripheral blood leukocytes serve as a disease biomarker of Friedreich’s ataxia? Antioxid Redox Signal. 2013;18:1303–6.PubMedCentralPubMedCrossRef
6.
7.
Olovnikov AM. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol. 1973;41:181–90.PubMedCrossRef
8.
Wellinger RJ, Ethier K, Labrecque P, Zakian VA. Evidence for a new step in telomere maintenance. Cell. 1996;85:423–33.PubMedCrossRef
9.
10.
11.
d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426:194–8.PubMedCrossRef
12.
McIlrath J, Bouffler SD, Samper E, Cuthbert A, Wojcik A, Szumiel I, et al. Telomere length abnormalities in mammalian radiosensitive cells. Cancer Res. 2001;61:912–5.PubMed
13.
Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell. 1997;90:785–95.PubMedCrossRef
14.
15.
Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13:1549–56.PubMedCrossRef
16.
Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, et al. The Friedreich’s ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet. 1999;8:425–30.PubMedCrossRef
17.
Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, de Lange T, et al. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet. 2012;8:e1002772.PubMedCentralPubMedCrossRef
18.
Rizki A, Lundblad V. Defects in mismatch repair promote telomerase-independent proliferation. Nature. 2001;411:713–6.PubMedCrossRef
19.
Schurks M, Buring J, Dushkes R, Gaziano JM, Zee RY, Kurth T. Telomere length and Parkinson’s disease in men: a nested case–control study. Eur J Neurol. 2014;21:93–9.PubMedCentralPubMedCrossRef
20.
Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D, et al. Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiol Aging. 2003;24:77–84.PubMedCrossRef
21.
van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell. 1998;92:401–13.PubMedCrossRef
22.
Hsu HL, Gilley D, Galande SA, Hande MP, Allen B, Kim SH, et al. Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev. 2000;14:2807–12.PubMedCentralPubMedCrossRef
23.
Bailey SM, Meyne J, Chen DJ, Kurimasa A, Li GC, Lehnert BE, et al. DNA double-strand break repair proteins are required to cap the ends of mammalian chromosomes. Proc Natl Acad Sci U S A. 1999;96:14899–904.PubMedCentralPubMedCrossRef
24.
Gilley D, Tanaka H, Hande MP, Kurimasa A, Li GC, Oshimura M, et al. DNA-PKcs is critical for telomere capping. Proc Natl Acad Sci U S A. 2001;98:15084–8.PubMedCentralPubMedCrossRef
25.
Goytisolo FA, Samper E, Edmonson S, Taccioli GE, Blasco MA. The absence of the dna-dependent protein kinase catalytic subunit in mice results in anaphase bridges and in increased telomeric fusions with normal telomere length and G-strand overhang. Mol Cell Biol. 2001;21:3642–51.PubMedCentralPubMedCrossRef
26.
Joenje H, Patel KJ. The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet. 2001;2:446–57.PubMedCrossRef
27.
Lansdorp PM. Repair of telomeric DNA prior to replicative senescence. Mech Ageing Dev. 2000;118:23–34.PubMedCrossRef
28.
Shen J, Loeb LA. Unwinding the molecular basis of the Werner syndrome. Mech Ageing Dev. 2001;122:921–44.PubMedCrossRef
29.
30.
Deng Z, Glousker G, Molczan A, Fox AJ, Lamm N, Dheekollu J, et al. Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome. Proc Natl Acad Sci U S A. 2013;110:E3408–16.PubMedCentralPubMedCrossRef
31.
Vannier JB, Sandhu S, Petalcorin MI, Wu X, Nabi Z, Ding H, et al. RTEL1 is a replisome-associated helicase that promotes telomere and genome-wide replication. Science. 2013;342:239–42.PubMedCrossRef
32.
Gari K, Leon Ortiz AM, Borel V, Flynn H, Skehel JM, Boulton SJ. MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA metabolism. Science. 2012;337:243–5.PubMedCrossRef
33.
Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M, et al. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol. 2006;8:416–24.PubMedCrossRef
34.
Benetti R, Garcia-Cao M, Blasco MA. Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nat Genet. 2007;39:243–50.PubMedCrossRef
35.
36.
Guan JZ, Guan WP, Maeda T, Makino N. The Subtelomere of Short Telomeres is Hypermethylated in Alzheimer’s Disease. Aging Dis. 2012;3:164–70.PubMedCentralPubMed
37.
Maeda T, Guan JZ, Oyama J, Higuchi Y, Makino N. Aging-associated alteration of subtelomeric methylation in Parkinson’s disease. J Gerontol A Biol Sci Med Sci. 2009;64:949–55.PubMedCrossRef
38.
Guan JZ, Maeda T, Sugano M, Oyama J, Higuchi Y, Suzuki T, et al. A percentage analysis of the telomere length in Parkinson’s disease patients. J Gerontol A Biol Sci Med Sci. 2008;63:467–73.PubMedCrossRef
39.
Hemann MT, Strong MA, Hao LY, Greider CW. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell. 2001;107:67–77.PubMedCrossRef
40.
Cherif H, Tarry JL, Ozanne SE, Hales CN. Ageing and telomeres: a study into organ- and gender-specific telomere shortening. Nucleic Acids Res. 2003;31:1576–83.PubMedCentralPubMedCrossRef
41.
Maeda T, Guan JZ, Oyama J, Higuchi Y, Makino N. Age-related changes in subtelomeric methylation in the normal Japanese population. J Gerontol A Biol Sci Med Sci. 2009;64:426–34.PubMedCrossRef
42.
Anjomani Virmouni S, Sandi C, Al-Mahdawi S, Pook MA. Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia. PLoS One. 2014;9:e107416.PubMedCentralPubMedCrossRef
43.
Sandi C, Sandi M, Jassal H, Ezzatizadeh V, Anjomani-Virmouni S, Al-Mahdawi S, et al. Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models. PLoS One. 2014;9:e89488.PubMedCentralPubMedCrossRef
44.
Cholewa D, Stiehl T, Schellenberg A, Bokermann G, Joussen S, Koch C, et al. Expansion of adipose mesenchymal stromal cells is affected by human platelet lysate and plating density. Cell Transplant. 2011;20:1409–22.PubMedCrossRef
45.
Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 2009;4:1798–806.PubMedCrossRef
46.
O'Callaghan NJ, Fenech M. A quantitative PCR method for measuring absolute telomere length. Biol Proced Online. 2011;13:3-9222–13-3.
47.
Cabuy E, Newton C, Roberts T, Newbold R, Slijepcevic P. Identification of subpopulations of cells with differing telomere lengths in mouse and human cell lines by flow FISH. Cytometry A. 2004;62:150–61.PubMedCrossRef
48.
Bailey SM, Cornforth MN, Ullrich RL, Goodwin EH. Dysfunctional mammalian telomeres join with DNA double-strand breaks. DNA Repair (Amst). 2004;3:349–57.CrossRef
49.
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21.PubMedCrossRef
50.
Yasaei H, Slijepcevic P. Defective Artemis causes mild telomere dysfunction. Genome Integr. 2010;1:3-9414–1-3.CrossRef
51.
Ducrest AL, Amacker M, Mathieu YD, Cuthbert AP, Trott DA, Newbold RF, et al. Regulation of human telomerase activity: repression by normal chromosome 3 abolishes nuclear telomerase reverse transcriptase transcripts but does not affect c-Myc activity. Cancer Res. 2001;61:7594–602.PubMed
Metadata
Title
Identification of telomere dysfunction in Friedreich ataxia
Authors
Sara Anjomani Virmouni
Sahar Al-Mahdawi
Chiranjeevi Sandi
Hemad Yasaei
Paola Giunti
Predrag Slijepcevic
Mark A. Pook
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2015
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-015-0019-6

Other articles of this Issue 1/2015

Molecular Neurodegeneration 1/2015 Go to the issue

Research Article

Studies of lipopolysaccharide effects on the induction of α-synuclein pathology by exogenous fibrils in transgenic mice

Research article

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator

Review

TREM2 in CNS homeostasis and neurodegenerative disease

Research article

Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer’s pathophysiology and susceptibility

Research article

Analysis of in vivo turnover of tau in a mouse model of tauopathy

Research article

The RAB39B p.G192R mutation causes X-linked dominant Parkinson’s disease