Altered Gene Expression and DNA Damage in Peripheral Blood Cells from Friedreich's Ataxia Patients: Cellular Model of Pathology
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.
Vyšlo v časopise:
Altered Gene Expression and DNA Damage in Peripheral Blood Cells from Friedreich's Ataxia Patients: Cellular Model of Pathology. PLoS Genet 6(1): e32767. doi:10.1371/journal.pgen.1000812
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1000812
Souhrn
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.
Zdroje
1. CampuzanoV
MonterminiL
LutzY
CovaL
HindelangC
1997 Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 6 1771 1780
2. CampuzanoV
MonterminiL
MoltoMD
PianeseL
CosseeM
1996 Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271 1423 1427
3. OhshimaK
MonterminiL
WellsRD
PandolfoM
1998 Inhibitory effects of expanded GAA.TTC triplet repeats from intron I of the Friedreich ataxia gene on transcription and replication in vivo. J Biol Chem 273 14588 14595
4. BidichandaniSI
AshizawaT
PatelPI
1998 The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. Am J Hum Genet 62 111 121
5. MuhlenhoffU
RichhardtN
RistowM
KispalG
LillR
2002 The yeast frataxin homolog Yfh1p plays a specific role in the maturation of cellular Fe/S proteins. Hum Mol Genet 11 2025 2036
6. StehlingO
ElsasserHP
BruckelB
MuhlenhoffU
LillR
2004 Iron-sulfur protein maturation in human cells: evidence for a function of frataxin. Hum Mol Genet 13 3007 3015
7. SchulzJB
DehmerT
ScholsL
MendeH
HardtC
2000 Oxidative stress in patients with Friedreich ataxia. Neurology 55 1719 1721
8. WongA
YangJ
CavadiniP
GelleraC
LonnerdalB
1999 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 8 425 430
9. Chantrel-GroussardK
GeromelV
PuccioH
KoenigM
MunnichA
2001 Disabled early recruitment of antioxidant defenses in Friedreich's ataxia. Hum Mol Genet 10 2061 2067
10. ShoichetSA
BaumerAT
StamenkovicD
SauerH
PfeifferAF
2002 Frataxin promotes antioxidant defense in a thiol-dependent manner resulting in diminished malignant transformation in vitro. Hum Mol Genet 11 815 821
11. GakhO
ParkS
LiuG
MacomberL
ImlayJA
2006 Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity. Hum Mol Genet 15 467 479
12. NapoliE
TaroniF
CortopassiGA
2006 Frataxin, iron-sulfur clusters, heme, ROS, and aging. Antioxid Redox Signal 8 506 516
13. PuccioH
SimonD
CosseeM
Criqui-FilipeP
TizianoF
2001 Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 27 181 186
14. CalabreseV
LodiR
TononC
D'AgataV
SapienzaM
2005 Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia. J Neurol Sci 233 145 162
15. FouryF
CazzaliniO
1997 Deletion of the yeast homologue of the human gene associated with Friedreich's ataxia elicits iron accumulation in mitochondria. FEBS Lett 411 373 377
16. KarthikeyanG
SantosJH
GraziewiczMA
CopelandWC
IsayaG
2003 Reduction in frataxin causes progressive accumulation of mitochondrial damage. Hum Mol Genet 12 3331 3342
17. LamarcheJB
CoteM
LemieuxB
1980 The cardiomyopathy of Friedreich's ataxia morphological observations in 3 cases. Can J Neurol Sci 7 389 396
18. WaldvogelD
van GelderenP
HallettM
1999 Increased iron in the dentate nucleus of patients with Friedrich's ataxia. Ann Neurol 46 123 125
19. EmondM
LepageG
VanasseM
PandolfoM
2000 Increased levels of plasma malondialdehyde in Friedreich ataxia. Neurology 55 1752 1753
20. BradleyJL
HomayounS
HartPE
SchapiraAH
CooperJM
2004 Role of oxidative damage in Friedreich's ataxia. Neurochem Res 29 561 567
21. SeznecH
SimonD
BoutonC
ReutenauerL
HertzogA
2005 Friedreich ataxia: the oxidative stress paradox. Hum Mol Genet 14 463 474
22. Di ProsperoNA
BakerA
JeffriesN
FischbeckKH
2007 Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial. Lancet Neurol 6 878 886
23. MyersLM
LynchDR
FarmerJM
FriedmanLS
LawsonJA
2008 Urinary isoprostanes in Friedreich ataxia: lack of correlation with disease features. Mov Disord 23 1920 1922
24. MichaelS
PetrocineSV
QianJ
LamarcheJB
KnutsonMD
2006 Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia. Cerebellum 5 257 267
25. TanG
NapoliE
TaroniF
CortopassiG
2003 Decreased expression of genes involved in sulfur amino acid metabolism in frataxin-deficient cells. Hum Mol Genet 12 1699 1711
26. CoppolaG
ChoiSH
SantosMM
MirandaCJ
TentlerD
2006 Gene expression profiling in frataxin deficient mice: microarray evidence for significant expression changes without detectable neurodegeneration. Neurobiol Dis 22 302 311
27. SchoenfeldRA
NapoliE
WongA
ZhanS
ReutenauerL
2005 Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells. Hum Mol Genet 14 3787 3799
28. HarrillAH
WatkinsPB
SuS
RossPK
HarbourtDE
2009 Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res
29. TusherVG
TibshiraniR
ChuG
2001 Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98 5116 5121
30. EfronB
TibshiraniR
2006 On testing the significance of sets of genes. Tech report 1 32
31. SubramanianA
TamayoP
MoothaVK
MukherjeeS
EbertBL
2005 Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102 15545 15550
32. HuT
GibsonDP
CarrGJ
TorontaliSM
TiesmanJP
2004 Identification of a gene expression profile that discriminates indirect-acting genotoxins from direct-acting genotoxins. Mutat Res 549 5 27
33. SantosJH
MeyerJN
MandavilliBS
Van HoutenB
2006 Quantitative PCR-based measurement of nuclear and mitochondrial DNA damage and repair in mammalian cells. Methods Mol Biol 314 183 199
34. YakesFM
Van HoutenB
1997 Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci U S A 94 514 519
35. SantosJH
HunakovaL
ChenY
BortnerC
Van HoutenB
2003 Cell sorting experiments link persistent mitochondrial DNA damage with loss of mitochondrial membrane potential and apoptotic cell death. J Biol Chem 278 1728 1734
36. MandavilliBS
BoldoghI
Van HoutenB
2005 3-nitropropionic acid-induced hydrogen peroxide, mitochondrial DNA damage, and cell death are attenuated by Bcl-2 overexpression in PC12 cells. Brain Res Mol Brain Res 133 215 223
37. MandavilliBS
AliSF
Van HoutenB
2000 DNA damage in brain mitochondria caused by aging and MPTP treatment. Brain Res 885 45 52
38. SalazarJJ
Van HoutenB
1997 Preferential mitochondrial DNA injury caused by glucose oxidase as a steady generator of hydrogen peroxide in human fibroblasts. Mutat Res 385 139 149
39. Van HoutenB
ChengS
ChenY
2000 Measuring gene-specific nucleotide excision repair in human cells using quantitative amplification of long targets from nanogram quantities of DNA. Mutat Res 460 81 94
40. FillaA
De MicheleG
CavalcantiF
PianeseL
MonticelliA
1996 The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet 59 554 560
41. PianeseL
TuranoM
Lo CasaleMS
De BiaseI
GiacchettiM
2004 Real time PCR quantification of frataxin mRNA in the peripheral blood leucocytes of Friedreich ataxia patients and carriers. J Neurol Neurosurg Psychiatry 75 1061 1063
42. ChouJW
ZhouT
KaufmannWK
PaulesRS
BushelPR
2007 Extracting gene expression patterns and identifying co-expressed genes from microarray data reveals biologically responsive processes. BMC Bioinformatics 8 427
43. TrouillasP
TakayanagiT
HallettM
CurrierRD
SubramonySH
1997 International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 145 205 211
44. OnukiJ
ChenY
TeixeiraPC
SchumacherRI
MedeirosMH
2004 Mitochondrial and nuclear DNA damage induced by 5-aminolevulinic acid. Arch Biochem Biophys 432 178 187
45. BurnettR
MelanderC
PuckettJW
SonLS
WellsRD
2006 DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA.TTC repeats in Friedreich's ataxia. Proc Natl Acad Sci U S A 103 11497 11502
46. LodiR
CooperJM
BradleyJL
MannersD
StylesP
1999 Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci U S A 96 11492 11495
47. VorgerdM
ScholsL
HardtC
RistowM
EpplenJT
2000 Mitochondrial impairment of human muscle in Friedreich ataxia in vivo. Neuromuscul Disord 10 430 435
48. ThierbachR
SchulzTJ
IskenF
VoigtA
MietznerB
2005 Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice. Hum Mol Genet 14 3857 3864
49. LewisPD
CorrJB
ArlettCF
HarcourtSA
1979 Increased sensitivity to gamma irradiation of skin fibroblasts in Friedreich's ataxia. Lancet 2 474 475
50. EvansHJ
Vijayalaxmi
PentlandB
NewtonMS
1983 Mutagen hypersensitivity in Friedreich's ataxia. Ann Hum Genet 47 193 204
51. FinkelT
HolbrookNJ
2000 Oxidants, oxidative stress and the biology of ageing. Nature 408 239 247
52. SchulzTJ
ThierbachR
VoigtA
DrewesG
MietznerB
2006 Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited. J Biol Chem 281 977 981
53. De PasT
MartinelliG
De BraudF
PeccatoriF
CataniaC
1999 Friedreich's ataxia and intrathecal chemotherapy in a patient with lymphoblastic lymphoma. Ann Oncol 10 1393
54. KiddA
ColemanR
WhitefordM
BarronLH
SimpsonSA
2001 Breast cancer in two sisters with Friedreich's ataxia. Eur J Surg Oncol 27 512 514
55. AckroydR
ShorthouseAJ
StephensonTJ
1996 Gastric carcinoma in siblings with Friedreich's ataxia. Eur J Surg Oncol 22 301 303
56. BarrH
PageR
TaylorW
1986 Primary small bowel ganglioneuroblastoma and Friedreich's ataxia. J R Soc Med 79 612 613
57. LillR
MuhlenhoffU
2008 Maturation of iron-sulfur proteins in eukaryotes: mechanisms, connected processes, and diseases. Annu Rev Biochem 77 669 700
58. KlingeS
HirstJ
MamanJD
KrudeT
PellegriniL
2007 An iron-sulfur domain of the eukaryotic primase is essential for RNA primer synthesis. Nat Struct Mol Biol 14 875 877
59. LukianovaOA
DavidSS
2005 A role for iron-sulfur clusters in DNA repair. Curr Opin Chem Biol 9 145 151
60. RudolfJ
MakrantoniV
IngledewWJ
StarkMJ
WhiteMF
2006 The DNA repair helicases XPD and FancJ have essential iron-sulfur domains. Mol Cell 23 801 808
61. SturmB
BistrichU
SchranzhoferM
SarseroJP
RauenU
2005 Friedreich's ataxia, no changes in mitochondrial labile iron in human lymphoblasts and fibroblasts: a decrease in antioxidative capacity? J Biol Chem 280 6701 6708
62. PaupeV
DassaEP
GoncalvesS
AuchereF
LonnM
2009 Impaired nuclear Nrf2 translocation undermines the oxidative stress response in friedreich ataxia. PLoS ONE 4 e4253
63. NiedernhoferLJ
GarinisGA
RaamsA
LalaiAS
RobinsonAR
2006 A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444 1038 1043
64. PaschenW
ProudCG
MiesG
2007 Shut-down of translation, a global neuronal stress response: mechanisms and pathological relevance. Curr Pharm Des 13 1887 1902
65. MukhopadhyayD
RiezmanH
2007 Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315 201 205
66. HerrmannJ
LermanLO
LermanA
2007 Ubiquitin and ubiquitin-like proteins in protein regulation. Circ Res 100 1276 1291
67. ZeebergBR
FengW
WangG
WangMD
FojoAT
2003 GoMiner: a resource for biological interpretation of genomic and proteomic data. Genome Biol 4 R28
68. DennisGJr
ShermanBT
HosackDA
YangJ
GaoW
2003 DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4 P3
69. EisenMB
SpellmanPT
BrownPO
BotsteinD
1998 Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 95 14863 14868
70. HeidCA
StevensJ
LivakKJ
WilliamsPM
1996 Real time quantitative PCR. Genome Res 6 986 994
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2010 Číslo 1
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- A Major Role of the RecFOR Pathway in DNA Double-Strand-Break Repair through ESDSA in
- Kidney Development in the Absence of and Requires
- The Werner Syndrome Protein Functions Upstream of ATR and ATM in Response to DNA Replication Inhibition and Double-Strand DNA Breaks
- Alternative Epigenetic Chromatin States of Polycomb Target Genes