Skip to main content
SpringerLink
Log in

Friedreich Ataxia: An Update on Animal Models, Frataxin Function and Therapies

  • Chapter
  • First Online:
Inherited Neuromuscular Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 652))

Abstract

Friedreich ataxia (FRDA) is an autosomal recessive progressively debilitating degenerative disease that principally affects the nervous system and the heart. Although FRDA is considered a rare disease, is the most common inherited ataxia. It is caused by loss-of-function mutations in the FXN gene, mainly an expanded GAA triplet repeat in the intron 1. The genetic defect results in the reduction of frataxin levels, a protein targeted to the mitochondria. Frataxin deficiency leads to mitochondrial dysfunction, oxidative damage and iron accumulation. Studies of the yeast and animal models of the disease have led to propose several different roles for frataxin. Animal models have also been important for dissecting the steps of pathogenesis in FRDA and they are essential for the development of effective therapies. Currently, antioxidant and iron chelation therapies are under evaluation in clinical trials. Gene reactivation, gene therapy and protein replacement strategies for FRDA are promising approaches.

This review focuses on the current models developed for FRDA, the different roles proposed for frataxin and the progress of potential treatment strategies for the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Friedreich N. Über degenerative Atrophie der spinalen Hinterstránge. Virchows Arch Pathol Anat 1863;27:1–26.

    Article  Google Scholar 

  2. Friedreich N. Über degenerative Atrophie der spinalen Hinterstränge. Virchows Arch Pathol Anat 1863;26(433–459).

    Google Scholar 

  3. Lopez-Arlandis JM, Vilchez JJ, Palau F, et al. Friedreich’s ataxia: an epidemiological study in Valencia, Spain, based on consanguinity analysis. Neuroepidemiology 1995;14(1):14–19.

    Article  CAS  PubMed  Google Scholar 

  4. Polo JM, Calleja J, Combarros O, et al. Hereditary ataxias and paraplegias in Cantabria, Spain. An epidemiological and clinical study. Brain 1991; 114 ( Pt 2):855–866.

    Article  PubMed  Google Scholar 

  5. Durr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med 1996;335 (16):1169–1175.

    Article  CAS  PubMed  Google Scholar 

  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 (5254):1423–1427.

    Article  CAS  PubMed  Google Scholar 

  7. Chamberlain S, Shaw J, Rowland A, et al. Mapping of mutation causing Friedreich’s ataxia to human chromosome 9. Nature 1988;334(6179):248–250.

    Article  CAS  PubMed  Google Scholar 

  8. Cossee M, Schmitt M, Campuzano V, et al. Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: founder effect and premutations. Proc Natl Acad Sci U S A 1997;94(14):7452–7457.

    Article  CAS  PubMed  Google Scholar 

  9. Montermini L, Andermann E, Labuda M, et al. The Friedreich ataxia GAA triplet repeat: premutation and normal alleles. Hum Mol Genet 1997;6(8):1261–1266.

    Article  CAS  PubMed  Google Scholar 

  10. Bidichandani SI, Ashizawa T, Patel PI. Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. Am J Hum Genet 1997;60(5):1251–1256.

    CAS  PubMed  Google Scholar 

  11. 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(11):1771–1780.

    Article  CAS  PubMed  Google Scholar 

  12. Grabczyk E, Mancuso M, Sammarco MC. A persistent RNA.DNA hybrid formed by transcription of the Friedreich ataxia triplet repeat in live bacteria, and by T7 RNAP in vitro. Nucleic Acids Res 2007;35(16):5351–5359.

    Article  CAS  PubMed  Google Scholar 

  13. Grabczyk E, Usdin K. The GAA*TTC triplet repeat expanded in Friedreich’s ataxia impedes transcription elongation by T7 RNA polymerase in a length and supercoil dependent manner. Nucleic Acids Res 2000;28(14):2815–2822.

    Article  CAS  PubMed  Google Scholar 

  14. Soragni E, Herman D, Dent SY, et al. Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia. Nucleic Acids Res 2008;36(19):6056–6065.

    Article  CAS  PubMed  Google Scholar 

  15. Al-Mahdawi S, Pook M, Chamberlain S. A novel missense mutation (L198R) in the Friedreich’s ataxia gene. Hum Mutat 2000;16(1):95.

    Article  CAS  PubMed  Google Scholar 

  16. Bartolo C, Mendell JR, Prior TW. Identification of a missense mutation in a Friedreich’s ataxia patient: implications for diagnosis and carrier studies. Am J Med Genet 1998;79(5):396–399.

    Article  CAS  PubMed  Google Scholar 

  17. Cossee M, Durr A, Schmitt M, et al. Friedreich’s ataxia: point mutations and clinical presentation of compound heterozygotes. Ann Neurol 1999;45(2):200–206.

    Article  CAS  PubMed  Google Scholar 

  18. De Castro M, Garcia-Planells J, Monros E, et al. Genotype and phenotype analysis of Friedreich’s ataxia compound heterozygous patients. Hum Genet 2000;106(1):86–92.

    Article  PubMed  Google Scholar 

  19. De Michele G, Filla A, Cavalcanti F, et al. Atypical Friedreich ataxia phenotype associated with a novel missense mutation in the X25 gene. Neurology 2000;54(2):496–499.

    PubMed  Google Scholar 

  20. Doudney K PM, Al-Mahdawi S, Carvajal J, Hillerman R, Chamberlain S. A novel site mutation (384+1G-A) in the Friedreich’s ataxia gene. Hum Mutat 1997;11:415.

    Google Scholar 

  21. Forrest SM, Knight M, Delatycki MB, et al. The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene. Neurogenetics 1998;1(4):253–257.

    Article  CAS  PubMed  Google Scholar 

  22. Labuda M PJaPM. A missense mutation (W155R) in an American patients with Friedreich ataxia. Hum Mutat 1999;13:506–507.

    Article  Google Scholar 

  23. McCormack ML, Guttmann RP, Schumann M, et al. Frataxin point mutations in two patients with Friedreich’s ataxia and unusual clinical features. J Neurol Neurosurg Psychiatry 2000;68(5):661–664.

    Article  CAS  PubMed  Google Scholar 

  24. Pook MA, Al-Mahdawi SA, Thomas NH, et al. Identification of three novel frameshift mutations in patients with Friedreich’s ataxia. J Med Genet 2000;37(11):E38.

    Article  CAS  PubMed  Google Scholar 

  25. Zhu D, Burke C, Leslie A, et al. Friedreich’s ataxia with chorea and myoclonus caused by a compound heterozygosity for a novel deletion and the trinucleotide GAA expansion. Mov Disord 2002;17(3):585–589.

    Article  PubMed  Google Scholar 

  26. Zuhlke C, Laccone F, Cossee M, et al. Mutation of the start codon in the FRDA1 gene: linkage analysis of three pedigrees with the ATG to ATT transversion points to a unique common ancestor. Hum Genet 1998;103(1):102–105.

    Article  CAS  PubMed  Google Scholar 

  27. Branda SS, Cavadini P, Adamec J, et al. Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase. J Biol Chem 1999;274(32):22763–22769.

    Article  CAS  PubMed  Google Scholar 

  28. Koutnikova H, Campuzano V, Koenig M. Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase. Hum Mol Genet 1998;7(9):1485–1489.

    Article  CAS  PubMed  Google Scholar 

  29. Schmucker S, Argentini M, Carelle-Calmels N, et al. The in vivo mitochondrial two-step maturation of human frataxin. Hum Mol Genet 2008;17(22):3521–35231.

    Article  CAS  PubMed  Google Scholar 

  30. Dhe-Paganon S, Shigeta R, Chi YI, et al. Crystal structure of human frataxin. J Biol Chem 2000;275(40):30753–30756.

    Article  CAS  PubMed  Google Scholar 

  31. Gibson TJ, Koonin EV, Musco G, et al. Friedreich’s ataxia protein: phylogenetic evidence for mitochondrial dysfunction. Trends Neurosci 1996;19(11):465–468.

    Article  CAS  PubMed  Google Scholar 

  32. Babcock M, de Silva D, Oaks R, et al. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science 1997;276(5319):1709–1712.

    Article  CAS  PubMed  Google Scholar 

  33. 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(2–3):373–377.

    Article  CAS  PubMed  Google Scholar 

  34. 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(4):345–351.

    Article  CAS  PubMed  Google Scholar 

  35. Radisky DC, Babcock MC, Kaplan J. The yeast frataxin homologue mediates mitochondrial iron efflux. Evidence for a mitochondrial iron cycle. J Biol Chem 1999;274(8):4497–4499.

    Article  CAS  PubMed  Google Scholar 

  36. Wilson RB, Roof DM. Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nat Genet 1997;16(4):352–357.

    Article  CAS  PubMed  Google Scholar 

  37. Cavadini P, Gellera C, Patel PI, et al. Human frataxin maintains mitochondrial iron homeostasis in Saccharomyces cerevisiae. Hum Mol Genet 2000;9(17):2523–2530.

    Article  CAS  PubMed  Google Scholar 

  38. Canizares J, Blanca JM, Navarro JA, et al. dfh is a Drosophila homolog of the Friedreich’s ataxia disease gene. Gene 2000;256(1–2):35–42.

    Article  CAS  PubMed  Google Scholar 

  39. Llorens JV, Navarro JA, Martinez-Sebastian MJ, et al. Causative role of oxidative stress in a Drosophila model of Friedreich ataxia. Faseb J 2007;21(2):333–344.

    Article  CAS  PubMed  Google Scholar 

  40. Anderson PR, Kirby K, Hilliker AJ, et al. RNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila. Hum Mol Genet 2005;14(22):3397–3405.

    Article  CAS  PubMed  Google Scholar 

  41. 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(8):1219–1226.

    Article  CAS  PubMed  Google Scholar 

  42. Das N, Levine RL, Orr WC, et al. Selectivity of protein oxidative damage during aging in Drosophila melanogaster. Biochem J 2001;360(Pt 1):209–216.

    Article  CAS  PubMed  Google Scholar 

  43. Prabhu HR, Krishnamurthy S. Ascorbate-dependent formation of hydroxyl radicals in the presence of iron chelates. Indian J Biochem Biophys 1993;30(5):289–292.

    CAS  PubMed  Google Scholar 

  44. Anderson PR, Kirby K, Orr WC, et al. Hydrogen peroxide scavenging rescues frataxin deficiency in a Drosophila model of Friedreich’s ataxia. Proc Natl Acad Sci U S A 2008;105(2):611–616.

    Article  CAS  PubMed  Google Scholar 

  45. Runko AP, Griswold AJ, Min KT. Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila. FEBS Lett 2008;582(5):715–719.

    Article  CAS  PubMed  Google Scholar 

  46. 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(3):549–562.

    Article  CAS  PubMed  Google Scholar 

  47. Ventura N, Rea S, Henderson ST, et al. Reduced expression of frataxin extends the lifespan of Caenorhabditis elegans. Aging Cell 2005;4(2):109–112.

    Article  CAS  PubMed  Google Scholar 

  48. Vazquez-Manrique RP, Gonzalez-Cabo P, Ros S, et al. Reduction of Caenorhabditis elegans frataxin increases sensitivity to oxidative stress, reduces lifespan, and causes lethality in a mitochondrial complex II mutant. Faseb J 2006;20(1):172–174.

    CAS  PubMed  Google Scholar 

  49. Zarse K, Schulz TJ, Birringer M, et al. Impaired respiration is positively correlated with decreased life span in Caenorhabditis elegans models of Friedreich Ataxia. Faseb J 2007;21(4):1271–1275.

    Google Scholar 

  50. 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(2):181–186.

    Article  CAS  PubMed  Google Scholar 

  51. Simon D, Seznec H, Gansmuller A, et al. Friedreich ataxia mouse models with progressive cerebellar and sensory ataxia reveal autophagic neurodegeneration in dorsal root ganglia. J Neurosci 2004;24(8):1987–1995.

    Article  CAS  PubMed  Google Scholar 

  52. Miranda CJ, Santos MM, Ohshima K, et al. Frataxin knockin mouse. FEBS Lett 2002;512(1–3):291–297.

    Article  CAS  PubMed  Google Scholar 

  53. Al-Mahdawi S, Pinto RM, Ruddle P, et al. GAA repeat instability in Friedreich ataxia YAC transgenic mice. Genomics 2004;84(2):301–310.

    Article  CAS  PubMed  Google Scholar 

  54. Al-Mahdawi S, Pinto RM, Varshney D, et al. GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology. Genomics 2006;88(5):580–590.

    Article  CAS  PubMed  Google Scholar 

  55. Clark RM, De Biase I, Malykhina AP, et al. The GAA triplet-repeat is unstable in the context of the human FXN locus and displays age-dependent expansions in cerebellum and DRG in a transgenic mouse model. Hum Genet 2007;120(5):633–640.

    Article  CAS  PubMed  Google Scholar 

  56. Waldvogel D, van Gelderen P, Hallett M. Increased iron in the dentate nucleus of patients with Friedrich’s ataxia. Ann Neurol 1999;46(1):123–125.

    Article  CAS  PubMed  Google Scholar 

  57. Lamarche JB, Cote M, Lemieux B. The cardiomyopathy of Friedreich’s ataxia morphological observations in 3 cases. Can J Neurol Sci 1980;7(4):389–396.

    CAS  PubMed  Google Scholar 

  58. Rotig A, de Lonlay P, Chretien D, et al. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet 1997;17(2):215–217.

    Article  CAS  PubMed  Google Scholar 

  59. Foury F. Low iron concentration and aconitase deficiency in a yeast frataxin homologue deficient strain. FEBS Lett 1999;456(2):281–284.

    Article  CAS  PubMed  Google Scholar 

  60. Park S, Gakh O, Mooney SM, et al. The ferroxidase activity of yeast frataxin. J Biol Chem 2002;277(41):38589–38595.

    Article  CAS  PubMed  Google Scholar 

  61. 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(33):31340–31351.

    Article  CAS  PubMed  Google Scholar 

  62. Cook JD, Bencze KZ, Jankovic AD, et al. Monomeric yeast frataxin is an iron-binding protein. Biochemistry 2006;45(25):7767–7777.

    Article  CAS  PubMed  Google Scholar 

  63. Nichol H, Gakh O, O’Neill HA, et al. Structure of frataxin iron cores: an X-ray absorption spectroscopic study. Biochemistry 2003;42(20):5971–5976.

    Article  CAS  PubMed  Google Scholar 

  64. 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(3):217–227.

    Article  CAS  PubMed  Google Scholar 

  65. Levi S, Corsi B, Bosisio M, et al. A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem 2001;276(27):24437–24440.

    Article  CAS  PubMed  Google Scholar 

  66. Campanella A, Isaya G, O’Neill HA, et al. The expression of human mitochondrial ferritin rescues respiratory function infrataxin-deficient yeast. Hum Mol Genet 2004;13(19):2279–2288.

    Article  CAS  PubMed  Google Scholar 

  67. 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(10):3813–3822.

    Article  CAS  PubMed  Google Scholar 

  68. Yoon T, Cowan JA. Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. J Biol Chem 2004;279(25):25943–25946.

    Article  CAS  PubMed  Google Scholar 

  69. 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(8):879–889.

    Article  CAS  PubMed  Google Scholar 

  70. 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(28):29101–29108.

    Article  CAS  PubMed  Google Scholar 

  71. Napoli E, Taroni F, Cortopassi GA. Frataxin, iron-sulfur clusters, heme, ROS, and aging. Antioxid Redox Signal 2006;8(3–4):506–516.

    Article  CAS  PubMed  Google Scholar 

  72. Napoli E, Morin D, Bernhardt R, et al. Hemin rescues adrenodoxin, heme a and cytochrome oxidase activity in frataxin-deficient oligodendroglioma cells. Biochim Biophys Acta 2007;1772(7):773–780.

    CAS  PubMed  Google Scholar 

  73. 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(17):2025–2036.

    Article  PubMed  Google Scholar 

  74. 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(21):2635–2643.

    Article  CAS  PubMed  Google Scholar 

  75. Lill R, Diekert K, Kaut A, et al. The essential role of mitochondria in the biogenesis of cellular iron-sulfur proteins. Biol Chem 1999;380(10):1157–1166.

    Article  CAS  PubMed  Google Scholar 

  76. Lill R, Muhlenhoff U. Iron-sulfur protein biogenesis in eukaryotes: components and mechanisms. Annu Rev Cell Dev Biol 2006;22:457–486.

    Article  CAS  PubMed  Google Scholar 

  77. 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(20):6078–6084.

    Article  CAS  PubMed  Google Scholar 

  78. 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(9):906–911.

    Article  CAS  PubMed  Google Scholar 

  79. 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(1–3):215–220.

    Article  CAS  PubMed  Google Scholar 

  80. Shan Y, Napoli E, Cortopassi G. Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum Mol Genet 2007;16(8):929–941.

    Article  CAS  PubMed  Google Scholar 

  81. Kondapalli KC, Kok NM, Dancis A, et al. Drosophila frataxin: an iron chaperone during cellular Fe-S cluster bioassembly. Biochemistry 2008;47(26):6917–6927.

    Article  CAS  PubMed  Google Scholar 

  82. Bulteau AL, O’Neill HA, Kennedy MC, et al. Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science 2004;305(5681):242–245.

    Article  CAS  PubMed  Google Scholar 

  83. Lodi R, Cooper JM, Bradley JL, et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci U S A 1999;96(20):11492–11495.

    Article  CAS  PubMed  Google Scholar 

  84. 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(22):12239–12243.

    Article  CAS  PubMed  Google Scholar 

  85. Busi MV, Zabaleta EJ, Araya A, et al. Functional and molecular characterization of the frataxin homolog from Arabidopsis thaliana. FEBS Lett 2004;576(1–2):141–144.

    Article  CAS  PubMed  Google Scholar 

  86. 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(15):2091–2098.

    Article  CAS  PubMed  Google Scholar 

  87. 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(5):590–596.

    Article  CAS  PubMed  Google Scholar 

  88. Hart PE, Lodi R, Rajagopalan B, et al. Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up. Arch Neurol 2005;62(4):621–626.

    Article  PubMed  Google Scholar 

  89. Geromel V, Darin N, Chretien D, et al. Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab 2002;77(1–2):21–30.

    Article  CAS  PubMed  Google Scholar 

  90. Mariotti C, Solari A, Torta D, et al. Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial. Neurology 2003;60(10):1676–1679.

    CAS  PubMed  Google Scholar 

  91. Ribai P, Pousset F, Tanguy ML, et al. Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up. Arch Neurol 2007;64(4):558–564.

    Article  PubMed  Google Scholar 

  92. Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, et al. Effect of idebenone on cardiomyopathy in Friedreich’s ataxia: a preliminary study. Lancet 1999;354(9177):477–479.

    Article  CAS  PubMed  Google Scholar 

  93. Di Prospero NA, Baker A, Jeffries N, et al. Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurol 2007;6(10):878–886.

    Article  PubMed  CAS  Google Scholar 

  94. Pineda M, Arpa J, Montero R, et al. Idebenone treatment in paediatric and adult patients with Friedreich ataxia: long-term follow-up. Eur J Paediatr Neurol 2008;12(6):470–475.

    Article  PubMed  Google Scholar 

  95. 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(7):4588–4596.

    Article  CAS  PubMed  Google Scholar 

  96. Jauslin ML, Meier T, Smith RA, et al. Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. Faseb J 2003;17(13):1972–1974.

    CAS  PubMed  Google Scholar 

  97. Boddaert N, Le Quan Sang KH, Rotig A, et al. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood 2007;110(1):401–408.

    Article  CAS  PubMed  Google Scholar 

  98. Kakhlon O, Manning H, Breuer W, et al. Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation. Blood 2008;112(13):5219–5227.

    Article  CAS  PubMed  Google Scholar 

  99. Goncalves S, Paupe V, Dassa EP, et al. Deferiprone targets aconitase: implication for Friedreich’s ataxia treatment. BMC Neurol 2008;8:20.

    Article  PubMed  CAS  Google Scholar 

  100. Lim CK, Kalinowski DS, Richardson DR. Protection against hydrogen peroxide-mediated cytotoxicity in Friedreich’s ataxia fibroblasts using novel iron chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone class. Mol Pharmacol 2008;74(1):225–235.

    Article  CAS  PubMed  Google Scholar 

  101. Siren AL, Ehrenreich H. Erythropoietin–a novel concept for neuroprotection. Eur Arch Psychiatry Clin Neurosci 2001;251(4):179–184.

    Article  CAS  PubMed  Google Scholar 

  102. Smith KJ, Bleyer AJ, Little WC, et al. The cardiovascular effects of erythropoietin. Cardiovasc Res 2003;59(3):538–548.

    Article  CAS  PubMed  Google Scholar 

  103. Sturm B, Stupphann D, Kaun C, et al. Recombinant human erythropoietin: effects on frataxin expression in vitro. Eur J Clin Invest 2005;35(11):711–717.

    Article  CAS  PubMed  Google Scholar 

  104. Grant L, Sun J, Xu H, et al. Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich’s ataxia. FEBS Lett 2006;580(22):5399–53405.

    Article  CAS  PubMed  Google Scholar 

  105. Dervan PB, Edelson BS. Recognition of the DNA minor groove by pyrrole-imidazole polyamides. Curr Opin Struct Biol 2003;13(3):284–299.

    Article  CAS  PubMed  Google Scholar 

  106. Burnett R, Melander C, Puckett JW, et al. DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA.TTC repeats in Friedreich’s ataxia. Proc Natl Acad Sci U S A 2006;103(31):11497–11502.

    Article  CAS  PubMed  Google Scholar 

  107. 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(1):72–81.

    Article  CAS  PubMed  Google Scholar 

  108. Herman D, Jenssen K, Burnett R, et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat Chem Biol 2006;2(10):551–8.

    Article  CAS  PubMed  Google Scholar 

  109. Rai M, Soragni E, Jenssen K, et al. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS ONE 2008;3(4):e1958.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work is supported by the Spanish Ministry of Science and Innovation and the Fondo de Investigación Sanitaria. The CIBER de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III.

Author information

Authors and Affiliations

  1. Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina de Valencia, CSIC, C/Jaume Roig 11, Valencia, Spain

    Pilar González-Cabo & Francesc Palau

  2. Departament Genètica, Facultat de Biologia, Universitat de València, Valencia, Burjassot, Spain

    José Vicente Llorens & Maria Dolores Moltó

Authors
  1. Pilar González-Cabo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. José Vicente Llorens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesc Palau
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Dolores Moltó
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pilar González-Cabo .

Editor information

Editors and Affiliations

  1. CIBERER-BIOBANK, Avda. Campanar 21, Valencia, 46009, Spain

    Carmen Espinós

  2. Lab. Neurobiología, Centro de Investigación Príncipe Felipe, Av. Autopista del Saler 16, Valencia, 46012, Spain

    Vicente Felipo

  3. Inst. Biomedicina, CSIC Valencia, C/ Jaime Roig 11, Valencia, 46010, Spain

    Francesc Palau

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

González-Cabo, P., Llorens, J.V., Palau, F., Moltó, M.D. (2009). Friedreich Ataxia: An Update on Animal Models, Frataxin Function and Therapies. In: Espinós, C., Felipo, V., Palau, F. (eds) Inherited Neuromuscular Diseases. Advances in Experimental Medicine and Biology, vol 652. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2813-6_17

Download citation

Publish with us

Policies and ethics

Search

Navigation