Seminars in Pediatric Neurology
Volume 13, Issue 3 , Pages 166-175 , September 2006

Iron Dysregulation in Friedreich Ataxia

  • Robert B. Wilson, MD, PhD

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Robert B. Wilson, MD, PhD, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Room 509A, Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19106.

References 

  1. Durr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. New Engl J Med. 1996;335:1169–1175
  2. Harding AE. Friedreich’s Ataxia: A clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain. 1981;104:589–620
  3. Klockgether T, Chamberlain S, Wullner U, et al. Late-onset Friedreich’s ataxia (Molecular genetics, clinical neurophysiology, and magnetic resonance imaging). Arch Neurol. 1993;50:803–806
  4. De Michele G, Filla A, Cavalcanti F, et al. Late onset Friedreich’s disease: clinical features and mapping of mutation to the FRDA locus. J Neurol Neurosurg Psychiatry. 1994;57:977–979
  5. Palau F, De Michele G, Vilchez JJ, et al. Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreich’s ataxia locus on chromosome 9q. Ann of Neurol. 1995;37:359–362
  6. Campuzano V, Montermini L, Molto MD, et al. Friedreich’s ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271:1423–1427[see comments]
  7. Pandolfo M. Molecular pathogenesis of Friedreich’s ataxia. Neurol Rev. 1999;56:1201–1208
  8. Ohshima K, Montermini L, Wells RD, et al. 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. 1998;273:14588–14595
  9. Sakamoto N, Sticky DNA. Self-association properties of long GAA (TTC repeats in R.R.Y triplex structures from Friedreich’s ataxia). Mol Cell. 1999;3:465–475
  10. Cossee M, Durr A, Schmitt M, et al. Friedreich’s ataxia: Point mutations and clinical presentation of compound heterozygotes. Ann Neurol. 1999;45:200–206
  11. Cossee M, Puccio H, Gansmuller A, et al. Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Hum Mol Genet. 2000;9:1219–1226
  12. Huynen MA, Snel B, Bork P, et al. The phylogenetic distribution of frataxin indicates a role in iron-sulfur cluster protein assembly. Hum Mol Genet. 2001;10:2463–2468
  13. Lodi R, Cooper JM, Bradley JL, et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Nat Acad Sci U S A. 1999;96:11492–11495
  14. Lodi R, Hart PE, Rajagopalan B, et al. Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich’s ataxia. Ann Neurol. 2001;49:590–596
  15. Lynch DR, Lech G, Farmer JM, et al. Near-infrared muscle spectroscopy in patients with Friedreich’s ataxia. Muscle Nerve. 2002;25:664–673
  16. Barbeau A. Friedreich’s ataxia 1980 an overview of the pathophysiology. Can J Neurol Sci. 1980;7:455–468
  17. Johns DR. Mitochondrial DNA and disease. N Engl J Med. 1995;333:638–644
  18. Barbeau A. The Quebec cooperative study of Friedreich’s ataxia: 1974-1984—10 years of research. Can J Neurol Sci. 1984;11:646–660
  19. Mastrogiacomo F, LaMarche J, Dozic S, et al. Immunoreactive levels of a-ketoglutarate dehydrogenase subunits in Friedreich’s ataxia and spinocerebellar ataxia type 1. Neurodegen. 1996;5:27–33
  20. Ouahchi K, Arita M, Kayden H, et al. Ataxia with isolated vitamin E defeciency is caused by mutations in the α-tocopherol transfer protein. Nature Genet. 1995;9:141–145
  21. Campuzano V, Montermini L, Lutz Y, et al. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet. 1997;6:1771–1780
  22. Koutnikova H, Campuzano V, Foury F, et al. Studies of human, mouse, and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet. 1997;16:345–351
  23. Babcock M, de Silva D, Oaks R, et al. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of Frataxin. Science. 1997;276:1709–1712
  24. Priller J, Scherzer CR, Faber PW, et al. Frataxin gene of Friedreich’s ataxia is targeted to mitochondria. Ann Neurol. 1997;42:265–269
  25. Wilson RB, Roof DM. Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nat Genet. 1997;16:352–357
  26. Cavadini P, Gellera C, Patel PI, et al. Human frataxin maintains mitochondrial iron homeostasis in Saccharomyces cerevisiae. Hum Mol Genet. 2000;9:2523–2530
  27. Foury F, Cazzalini O. Deletion of the yeast homologue of the human gene associated with Friedreich’s ataxia elicits iron accumulation in mitochondria. FEBS Lett. 1997;411:373–377
  28. Radisky DC, Babcock MC, Kaplan JK. The yeast frataxin homologue mediates mitochondrial iron efflux: Evidence for a mitochondrial iron cycle. J Biol Chem. 1999;274:4497–4499
  29. Foury F. Low iron concentration and aconitase deficiency in a yeast frataxin homologue deficient strain. FEBS Lett. 1999;456:281–284
  30. LaMarche JB, Cote M, Lemieux B. The cardiomyopathy of Friedreich’s ataxia morphological observations in 3 cases. Can J Neurol Sci. 1980;7:389–396
  31. Bradley JL, Blake JC, Chamberlain S, et al. Clinical, biochemical and molecular genetic correlations in Friedreich’s ataxia. Hum Mol Genet. 2000;9:275–282
  32. Delatycki MB, Camakaris J, Brooks H, et al. Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia. Ann Neurol. 1999;45:673–675
  33. Wong A, Yang J, Cavadini P, 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;8:425–430
  34. Wilson RB, Lynch DR, Fischbeck KH. Normal serum iron and ferritin concentrations in patients with Friedreich’s ataxia. Ann Neurol. 1998;44:132–134
  35. Horton AA, Fairhurst S. Lipid peroxidation and mechanisms of toxicity. CRC Crit Rev Toxicol. 1987;18:27–79
  36. Schulz JB, Dehmer T, Schols L, et al. Oxidative stress in patients with Friedreich ataxia [see comments]. Neurology. 2000;55:1719–1721
  37. Emond M, Lepage G, Vanasse M, et al. Increased levels of plasma malondialdehyde in Friedreich ataxia [see comments]. Neurology. 2000;55:1752–1753
  38. Patel PI, Isaya G. Friedreich ataxia: From GAA triplet-repeat expansion to frataxin deficiency. Am J Hum Genet. 2001;69:15–24
  39. Adamec J, Rusnak F, Owen WG, et al. Iron-dependent self-assembly of recombinant yeast frataxin: Implications for Friedreich Ataxia. Am J Hum Genet. 2000;67:549–562
  40. Cavadini P, O’Neill HA, Benada O, et al. Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Hum Mol Genet. 2002;11:217–227
  41. Gakh O, Adamec J, Gacy AM, et al. Physical evidence that yeast frataxin is an iron storage protein. Biochemistry. 2002;41:6798–6804
  42. Muhlenhoff U, Richhardt N, Ristow M, et al. The yeast frataxin homolog Yfh1p plays a specific role in the maturation of cellular Fe/S proteins. Hum Mol Genet. 2002;11:2025–2036
  43. Chen OS, Hemenway S, Kaplan J. Inhibition of Fe-S cluster biosynthesis decreases mitochondrial iron export: evidence that Yfh1p affects Fe-S cluster synthesis. Proc Natl Acad Sci U S A. 2002;99:12321–12326
  44. Duby G, Foury F, Ramazzotti A, et al. A non-essential function for yeast frataxin in iron-sulfur cluster assembly. Hum Mol Genet. 2002;11:2635–2643
  45. Muhlenhoff U, Gerber J, Richhardt N, et al. Components involved in assembly and dislocation of iron-sulfur clusters on the scaffold protein Isu1p. EMBO J. 2003;22:4815–4825
  46. Park S, Gakh O, O’Neill HA, et al. Yeast frataxin sequentially chaperones and stores iron by coupling protein assembly with iron oxidation. J Biol Chem. 2003;278:31340–31351
  47. Bulteau AL, O’Neill HA, Kennedy MC, et al. Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science. 2004;305:242–245
  48. Stehling O, Elsasser HP, Bruckel B, et al. Iron-sulfur protein maturation in human cells: Evidence for a function of frataxin. Hum Mol Genet. 2004;13:3007–3015
  49. Beinert H, Holm RH, Munck E. Iron-sulfur clusters: Nature’s modular, multipurpose structures. Science. 1997;277:653–659
  50. Lill R, Muhlenhoff U. Iron-sulfur-protein biogenesis in eukaryotes. Trends Biochem Sci. 2005;30:133–141
  51. Rouault TA, Tong WH. Iron-sulphur cluster biogenesis and mitochondrial iron homeostasis. Nat Rev Mol Cell Biol. 2005;6:345–351
  52. Gerber J, Muhlenhoff U, Lill R. An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1. Embo Rep. 2003;4:906–911
  53. Yoon T, Cowan JA. Iron-sulfur cluster biosynthesis (Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins). J Am Chem Soc. 2003;125:6078–6084
  54. Ramazzotti A, Vanmansart V, Foury F. Mitochondrial functional interactions between frataxin and Isu1p, the iron-sulfur cluster scaffold protein, in Saccharomyces cerevisiae. FEBS Lett. 2004;557:215–220
  55. Bulteau AL, Lundberg KC, Ikeda-Saito M, et al. Reversible redox-dependent modulation of mitochondrial aconitase and proteolytic activity during in vivo cardiac ischemia/reperfusion. Proc Natl Acad Sci U S A. 2005;102:5987–5991
  56. Rotig A, de Lonlay P, Chretien D, et al. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich’s ataxia. Nat Genet. 1997;17:215–217
  57. Rouault T, Klausner R. Regulation of iron metabolism in eukaryotes. Curr Top Cell Reg. 1997;35:1–19
  58. Lobmayr L, Brooks DG, Wilson RB. Increased IRP1 activity in Friedreich ataxia. Gene. 2005;354:157–161
  59. Seznec H, Simon D, Bouton C, et al. Friedreich ataxia: The oxidative stress paradox. Hum Mol Genet. 2005;14:463–474
  60. Meyron-Holtz EG, Ghosh MC, Rouault TA. Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo. Science. 2004;306:2087–2090
  61. Meyron-Holtz EG, Ghosh MC, Iwai K, et al. Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. Embo J. 2004;23:386–395
  62. Roy A, Solodovnikova N, Nicholson T, et al. A novel eukaryotic factor for cytosolic Fe-S cluster assembly. Embo J. 2003;22:4826–4835
  63. Balk J, Pierik AJ, Netz DJ, et al. The hydrogenase-like Nar1p is essential for maturation of cytosolic and nuclear iron-sulphur proteins. Embo J. 2004;23:2105–2115
  64. Hausmann A, Aguilar Netz DJ, Balk J, et al. The eukaryotic P loop NTPase Nbp35: An essential component of the cytosolic and nuclear iron-sulfur protein assembly machinery. Proc Natl Acad Sci U S A. 2005;102:3266–3271
  65. Balk J, Aguilar Netz DJ, Tepper K, et al. The essential WD40 protein Cia1 is involved in a late step of cytosolic and nuclear iron-sulfur protein assembly. Mol Cell Biol. 2005;25:10833–10841
  66. Land T, Rouault TA. Targeting of a human iron-sulfur cluster assembly enzyme, nifs, to different subcellular compartments is regulated through alternative AUG utilization. Mol Cell. 1998;2:807–815
  67. Tong WH, Rouault T. Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. Embo J. 2000;19:5692–5700
  68. Tong WH, Jameson GN, Huynh BH, et al. Subcellular compartmentalization of human Nfu, an iron-sulfur cluster scaffold protein, and its ability to assemble a [4Fe-4S] cluster. Proc Natl Acad Sci U S A. 2003;100:9762–9767
  69. Acquaviva F, De Biase I, Nezi L, et al. Extra-mitochondrial localisation of frataxin and its association with IscU1 during enterocyte-like differentiation of the human colon adenocarcinoma cell line Caco-2. J Cell Sci. 2005;118:3917–3924
  70. Condo I, Ventura N, Malisan F, et al. A pool of extramitochondrial frataxin that promotes cell survival. J Biol Chem. 2006;281:16750–16756
  71. Kiley PJ, Beinert H. The role of Fe-S proteins in sensing and regulation in bacteria. Curr Opin Microbiol. 2003;6:181–185
  72. Bouton C, Drapier JC. Iron regulatory proteins as NO signal transducers. Sci STKE. 2003;17:2003
  73. Chen OS, Crisp RJ, Valachovic M, et al. Transcription of the yeast iron regulon does not respond directly to iron but rather to iron-sulfur cluster biosynthesis. J Biol Chem. 2004;279:29513–29518
  74. Rutherford JC, Ojeda L, Balk J, et al. Activation of the iron regulon by the yeast Aft1/Aft2 transcription factors depends on mitochondrial but not cytosolic iron-sulfur protein biogenesis. J Biol Chem. 2005;280:10135–10140
  75. Ojeda L, Keller G, Muhlenhoff U, et al. Role of glutaredoxin-3 and glutaredoxin-4 in the iron-regulation of the Aft1 transcriptional activator in Saccharomyces cerevisiae. J Biol Chem. 2006;281:17661–17669
  76. Puccio H, Simon D, Cossee M, et al. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet. 2001;27:181–186
  77. Anderson PR, Kirby K, Hilliker AJ, et al. RNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila. Hum Mol Genet. 2005;14:3397–3405
  78. Dhe-Paganon S, Shigeta R, Chi YI, et al. Crystal structure of human frataxin. J Biol Chem. 2000;275:30753–30756
  79. He Y, Alam SL, Proteasa SV, et al. Yeast frataxin solution structure, iron binding, and ferrochelatase interaction. Biochemistry. 2004;43:16254–16262
  80. Cho SJ, Lee MG, Yang JK, et al. Crystal structure of Escherichia coli CyaY protein reveals a previously unidentified fold for the evolutionarily conserved frataxin family. Proc Natl Acad Sci U S A. 2000;97:8932–8937
  81. Musco G, Stier G, Kolmerer B, et al. Towards a structural understanding of Friedreich’s ataxia: The solution structure of frataxin. Structure. 2000;8:695–707
  82. Adinolfi S, Trifuoggi M, Politou AS, et al. A structural approach to understanding the iron-binding properties of phylogenetically different frataxins. Hum Mol Genet. 2002;11:1865–1877
  83. Bou-Abdallah F, Adinolfi S, Pastore A, et al. Iron binding and oxidation kinetics in frataxin CyaY of Escherichia coli. J Mol Biol. 2004;341:605–615
  84. Nichol H, Gakh O, O’Neill HA, et al. Structure of frataxin iron cores: an X-ray absorption spectroscopic study. Biochemistry. 2003;42:5971–5976
  85. Seznec H, Wilson RB, Puccio H. 2003 International Friedreich’s Ataxia Research Conference, 14-16 February 2003, Bethesda, MD, USA. Neuromuscul Disord. 2004;14:70–82
  86. Campanella A, Isaya G, O’Neill HA, et al. The expression of human mitochondrial ferritin rescues respiratory function in frataxin-deficient yeast. Hum Mol Genet. 2004;13:2279–2288
  87. O’Neill HA, Gakh O, Park S, et al. Assembly of human frataxin is a mechanism for detoxifying redox-active iron. Biochemistry. 2005;44:537–545
  88. Aloria K, Schilke B, Andrew A, et al. Iron-induced oligomerization of yeast frataxin homologue Yfh1 is dispensable in vivo. Embo Rep. 2004;5:1096–1101
  89. Nair M, Adinolfi S, Pastore C, et al. Solution structure of the bacterial frataxin ortholog, CyaY: Mapping the iron binding sites. Structure. 2004;12:2037–2048
  90. Gakh O, Park S, Liu G, et al. Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity. Hum Mol Genet. 2006;15:467–479
  91. Karthikeyan G, Santos JH, Graziewicz MA, et al. Reduction in frataxin causes progressive accumulation of mitochondrial damage. Hum Mol Genet. 2003;12:3331–3342
  92. Chantrel-Groussard K, Geromel V, Puccio H, et al. Disabled early recruitment of antioxidant defenses in Friedreich’s ataxia. Hum Mol Genet. 2001;10:2061–2067
  93. Jiralerspong S, Ge B, Hudson TJ, et al. Manganese superoxide dismutase induction by iron is impaired in Friedreich ataxia cells. FEBS Lett. 2001;509:101–105
  94. Irazusta V, Cabiscol E, Reverter-Branchat G, et al. Manganese is the link between frataxin and iron-sulfur deficiency in the yeast model of Friedreich’s ataxia. J Biol Chem. 2006;281:12227–12232
  95. Chen OS, Kaplan J. CCC1 suppresses mitochondrial damage in the yeast model of Friedreich’s ataxia by limiting mitochondrial iron accumulation. J Biol Chem. 2000;275:7626–7632
  96. Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482–488
  97. Korshunova YO, Eide D, Clark WG, et al. The IRT1 protein from Arabidopsis thaliana is a metal transporter with a broad substrate range. Plant Mol Biol. 1999;40:37–44
  98. Supek F, Supekova L, Nelson H, et al. A yeast manganese transporter related to the macrophage protein involved in conferring resistance to mycobacteria. Proc Natl Acad Sci U S A. 1996;93:5105–5110
  99. Yang M, Cobine PA, Molik S, et al. The effects of mitochondrial iron homeostasis on cofactor specificity of superoxide dismutase 2. Embo J. 2006;25:1775–1783
  100. Foury F, Roganti T. Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. J Biol Chem. 2002;277:24475–24483
  101. Muhlenhoff U, Stadler JA, Richhardt N, et al. A specific role of the yeast mitochondrial carriers MRS3/4p in mitochondrial iron acquisition under iron-limiting conditions. J Biol Chem. 2003;278:40612–40620
  102. Li L, Kaplan J. A mitochondrial-vacuolar signaling pathway in yeast that affects iron and copper metabolism. J Biol Chem. 2004;279:33653–33661
  103. Zhang Y, Lyver ER, Knight SA, et al. Frataxin and mitochondrial carrier proteins, Mrs3p and Mrs4p, cooperate in providing iron for heme synthesis. J Biol Chem. 2005;280:19794–19807
  104. Lesuisse E, Santos R, Matzanke BF, et al. Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1). Hum Mol Genet. 2003;12:879–889
  105. Morgan RO. Erythrocyte protoporphyrin levels in patients with Friedreich’s and other ataxias. Can J Neurol Sci. 1979;6:227–232
  106. Barbeau A. Friedreich’s disease 1982: Etiologic hypotheses a personal analysis. Can J Neurol Sci. 1982;9:243–263
  107. Becker EM, Greer JM, Ponka P, et al. Erythroid differentiation and protoporphyrin IX down-regulate frataxin expression in Friend cells: Characterization of frataxin expression compared to molecules involved in iron metabolism and hemoglobinization. Blood. 2002;99:3813–3822
  108. Lange H, Muhlenhoff U, Denzel M, et al. The heme synthesis defect of mutants impaired in mitochondrial iron-sulfur protein biogenesis is caused by reversible inhibition of ferrochelatase. J Biol Chem. 2004;279:29101–29108
  109. Yoon T, Cowan JA. Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. J Biol Chem. 2004;279:25943–25946
  110. Ristow M, Pfister MF, Yee AJ, et al. Frataxin activates mitochondrial energy conversion and oxidative phosphorylation. Proc Natl Acad Sci U S A. 2000;97:12239–12243
  111. Shoichet SA, Baumer AT, Stamenkovic D, et al. Frataxin promotes antioxidant defense in a thiol-dependent manner resulting in diminished malignant transformation in vitro. Hum Mol Genet. 2002;11:815–821
  112. Schulz TJ, Thierbach R, Voigt A, et al. Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited. J Biol Chem. 2006;281:977–981
  113. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269–270
  114. Gonzalez-Cabo P, Vazquez-Manrique RP, Garcia-Gimeno MA, et al. Frataxin interacts functionally with mitochondrial electron transport chain proteins. Hum Mol Genet. 2005;14:2091–2098
  115. Sazanov LA, Hinchliffe P. Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus. Science. 2006;311:1430–1436
  116. Wilson RB. Experimental therapeutics for Friedreich ataxia. In:  Wells RD,  Ashizawa TS editor. Genetic Instabilities and Neurological Diseases. Burlington, MA: Elsevier; 2006;
  117. Hart PE, Lodi R, Rajagopalan B, et al. Antioxidant treatment of patients with Friedreich ataxia: Four-year follow-up. Arch Neurol. 2005;62:621–626
  118. Hausse AO, Aggoun Y, Bonnet D, et al. Idebenone and reduced cardiac hypertrophy in Friedreich’s ataxia [see comments]. Heart. 2002;87:346–349
  119. Mariotti C, Solari A, Torta D, et al. Idebenone treatment in Friedreich patients: One-year-long randomized placebo-controlled trial. Neurology. 2003;60:1676–1679
  120. Buyse G, Mertens L, Di Salvo G, et al. Idebenone treatment in Friedreich’s ataxia: Neurological, cardiac, and biochemical monitoring. Neurology. 2003;60:1679–1681
  121. Kelso GF, Porteous CM, Coulter CV, et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: Antioxidant and antiapoptotic properties. J Biol Chem. 2001;276:4588–4596
  122. Smith RA, Porteous CM, Gane AM, et al. Delivery of bioactive molecules to mitochondria in vivo. Proc Natl Acad Sci U S A. 2003;100:5407–5412
  123. Grabczyk E, Usdin K. Alleviating transcript insufficiency caused by Friedreich’s ataxia triplet repeats. Nucleic Acids Res. 2000;28:4930–4937
  124. Napierala M, Bacolla A, Wells RD. Increased negative superhelical density in vivo enhances the genetic instability of triplet repeat sequences. J Biol Chem. 2005;280:37366–37376
  125. Sarsero JP, Li L, Wardan H, et al. Upregulation of expression from the FRDA genomic locus for the therapy of Friedreich ataxia. J Gene Med. 2003;5:72–81
  126. Sturm B, Stupphann D, Kaun C, et al. Recombinant human erythropoietin: Effects on frataxin expression in vitro. Eur J Clin Invest. 2005;35:711–717
  127. Gottesfeld JM, Turner JM, Dervan PB. Chemical approaches to control gene expression. Gene Expr. 2000;9:77–91
  128. Dervan PB, Edelson BS. Recognition of the DNA minor groove by pyrrole-imidazole polyamides. Curr Opin Struct Biol. 2003;13:284–299
  129. Richardson DR, Mouralian C, Ponka P, et al. Development of potential iron chelators for the treatment of Friedreich’s ataxia: Ligands that mobilize mitochondrial iron. Biochim Biophys Acta. 2001;1536:133–140
  130. Richardson DR. Friedreich’s ataxia: Iron chelators that target the mitochondrion as a therapeutic strategy?. Expert Opin Investig Drugs. 2003;12:235–245
  131. Voncken M, Ioannou P, Delatycki MB. Friedreich ataxia-update on pathogenesis and possible therapies. Neurogenetics. 2004;5:1–8

 Supported in part by grants from the National Institutes of Health, the Friedreich’s Ataxia Research Alliance, the National Ataxia Foundation, and Seek-A-Miracle.

PII: S1071-9091(06)00104-5

doi: 10.1016/j.spen.2006.08.005

Seminars in Pediatric Neurology
Volume 13, Issue 3 , Pages 166-175 , September 2006

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