title: PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.
abstract: BACKGROUND
  Cells from individuals with Friedreich's ataxia (FRDA) show reduced activities of antioxidant enzymes and cannot up-regulate their expression when exposed to oxidative stress. This blunted antioxidant response may play a central role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARgamma) Coactivator 1-alpha (PGC-1alpha), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models.
  
  
  RESULTS
  We used primary fibroblasts from FRDA patients and the knock in-knock out animal model for the disease (KIKO mouse) to determine basal superoxide dismutase 2 (SOD2) levels and the response to oxidative stress induced by the addition of hydrogen peroxide. We measured the same parameters after pharmacological stimulation of PGC-1alpha. Compared to control cells, PGC-1alpha and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1alpha direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1alpha activation with the PPARgamma agonist (Pioglitazone) or with a cAMP-dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction. Treatment of the KIKO mice with Pioglitazone significantly up-regulates SOD2 in cerebellum and spinal cord.
  
  
  CONCLUSIONS
  PGC-1alpha down-regulation is likely to contribute to the blunted antioxidant response observed in cells from FRDA patients. This response can be restored by AMPK and PPARgamma agonists, suggesting a potential therapeutic approach for FRDA.
authors.affiliation: Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Daniele
authors.initials: D
authors.lastname: Marmolino
authors.forename: Mario
authors.initials: M
authors.lastname: Manto
authors.forename: Fabio
authors.initials: F
authors.lastname: Acquaviva
authors.forename: Paola
authors.initials: P
authors.lastname: Vergara
authors.forename: Ajay
authors.initials: A
authors.lastname: Ravella
authors.forename: Antonella
authors.initials: A
authors.lastname: Monticelli
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases; D015536:Down-Regulation / Q000235:genetics*; D005621:Friedreich Ataxia / Q000378:metabolism / Q000473:pathology*; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013482:Superoxide Dismutase / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics*; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D017868:Cyclic AMP-Dependent Protein Kinases; D006360:Heat-Shock Proteins; D006861:Hydrogen Peroxide; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013482:Superoxide Dismutase; D014157:Transcription Factors; D000099156:Superoxide Dismutase 2; C486497:PPARGC1A protein, human
references.citation: Diabetes. 2006 Jan;55(1):120-7
references.pmid: 16380484
references.citation: Cardiovasc Res. 2005 Jun 1;66(3):562-73
references.pmid: 15914121
references.citation: Science. 1996 Mar 8;271(5254):1423-7
references.pmid: 8596916
references.citation: Biochem Soc Symp. 1999;66:99-110
references.pmid: 10989661
references.citation: J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S20-7
references.pmid: 17567459
references.citation: Nat Chem Biol. 2006 Aug;2(8):406-14
references.pmid: 16850017
references.citation: J Biol Chem. 2009 May 22;284(21):14476-84
references.pmid: 19324885
references.citation: Exp Gerontol. 2010 May;45(5):336-42
references.pmid: 20085804
references.citation: Eur J Clin Invest. 2001 Nov;31(11):1007-11
references.pmid: 11737244
references.citation: Cell Metab. 2005 Apr;1(4):259-71
references.pmid: 16054070
references.citation: Nat Chem Biol. 2006 Oct;2(10):551-8
references.pmid: 16921367
references.citation: Semin Pediatr Neurol. 2003 Sep;10(3):163-72
references.pmid: 14653404
references.citation: Biochem Biophys Res Commun. 2009 Jan 30;379(1):43-8
references.pmid: 19084501
references.citation: Neurochem Int. 2009 Dec;55(7):496-504
references.pmid: 19442697
references.citation: Hum Mol Genet. 2007 Nov 15;16(22):2651-8
references.pmid: 17597094
references.citation: Mol Cell. 1999 Apr;3(4):465-75
references.pmid: 10230399
references.citation: Hum Mol Genet. 1999 Mar;8(3):425-30
references.pmid: 9949201
references.citation: Genomics. 1999 Nov 15;62(1):98-102
references.pmid: 10585775
references.citation: Neurology. 1988 Aug;38(8):1292-6
references.pmid: 3041313
references.citation: Biochemistry. 2003 May 27;42(20):5971-6
references.pmid: 12755598
references.citation: Mov Disord. 2000 Nov;15(6):1255-8
references.pmid: 11104216
references.citation: Biochemistry. 2006 Jun 27;45(25):7767-77
references.pmid: 16784228
references.citation: Hum Mol Genet. 2001 Oct 1;10(21):2463-8
references.pmid: 11689493
references.citation: Endocr Rev. 2006 Dec;27(7):728-35
references.pmid: 17018837
references.citation: Curr Opin Lipidol. 2009 Apr;20(2):98-105
references.pmid: 19276888
references.citation: Cell Metab. 2008 Sep;8(3):249-56
references.pmid: 18762025
references.citation: Acta Physiol (Oxf). 2009 May;196(1):147-54
references.pmid: 19245653
references.citation: Cerebellum. 2009 Sep;8(3):245-59
references.pmid: 19165552
references.citation: Hum Mol Genet. 2001 Sep 15;10(19):2061-7
references.pmid: 11590123
references.citation: Free Radic Biol Med. 2008 Nov 15;45(10):1375-83
references.pmid: 18824091
references.citation: FEBS Lett. 2001 Nov 30;509(1):101-5
references.pmid: 11734214
references.citation: J Neurol. 1990 Oct;237(6):345-51
references.pmid: 2277267
references.citation: PLoS One. 2009;4(1):e4253
references.pmid: 19158945
references.citation: Hum Mol Genet. 2001 Sep 1;10(18):1935-44
references.pmid: 11555630
references.citation: Cell. 1999 Jul 9;98(1):115-24
references.pmid: 10412986
references.citation: Hum Mol Genet. 2000 May 1;9(8):1219-26
references.pmid: 10767347
references.citation: Free Radic Biol Med. 2007 May 15;42(10):1561-70
references.pmid: 17448903
references.citation: J Med Genet. 2000 Jan;37(1):1-8
references.pmid: 10633128
references.citation: Hum Mol Genet. 2009 Jul 1;18(13):2452-61
references.pmid: 19376812
references.citation: Am J Physiol Cell Physiol. 2009 Jul;297(1):C217-25
references.pmid: 19439529
references.citation: J Biol Chem. 2003 Aug 15;278(33):31340-51
references.pmid: 12732649
references.citation: J Biol Chem. 2003 Jul 18;278(29):26597-603
references.pmid: 12734177
references.citation: J Mol Biol. 2004 Aug 6;341(2):605-15
references.pmid: 15276847
references.citation: Adv Microb Physiol. 2008;53:231-67
references.pmid: 17707146
references.citation: Exp Physiol. 2003 Jan;88(1):33-40
references.pmid: 12525853
references.citation: J Biol Chem. 2004 Jun 18;279(25):25943-6
references.pmid: 15123683
references.citation: Mol Cell Biol. 2000 Apr;20(7):2411-22
references.pmid: 10713165
references.citation: Hum Mol Genet. 2003 Jul 15;12(14):1699-711
references.pmid: 12837693
references.citation: Nat Genet. 2001 Feb;27(2):181-6
references.pmid: 11175786
references.citation: FEBS Lett. 1997 Jul 14;411(2-3):373-7
references.pmid: 9271239
references.citation: Toxicol Appl Pharmacol. 2010 Apr 1;244(1):77-83
references.pmid: 19501608
references.citation: PLoS Biol. 2005 Apr;3(4):e101
references.pmid: 15760270
references.citation: Genomics. 2006 Nov;88(5):580-90
references.pmid: 16919418
references.citation: Neurology. 2000 Dec 12;55(11):1719-21
references.pmid: 11113228
references.citation: Cell. 2004 Oct 1;119(1):121-35
references.pmid: 15454086
references.citation: Curr Opin Cell Biol. 1999 Dec;11(6):689-94
references.pmid: 10600710
references.citation: Neurogenetics. 2001 Oct;3(4):185-93
references.pmid: 11714098
references.citation: Structure. 2006 Oct;14(10):1535-46
references.pmid: 17027502
references.citation: PLoS One. 2008;3(10):e3614
references.pmid: 18974883
references.citation: J Neurol. 2009 Mar;256 Suppl 1:18-24
references.pmid: 19283346
references.citation: Endocr Rev. 2003 Feb;24(1):78-90
references.pmid: 12588810
references.citation: Hum Mol Genet. 2003 Dec 15;12(24):3331-42
references.pmid: 14570713
references.citation: Nat Rev Mol Cell Biol. 2005 Apr;6(4):345-51
references.pmid: 15803140
references.citation: Physiol Rev. 1997 Jul;77(3):731-58
references.pmid: 9234964
references.citation: PLoS One. 2008 Apr 09;3(4):e1958
references.pmid: 18463734
references.citation: Aging Cell. 2008 Jan;7(1):101-11
references.pmid: 18031569
references.citation: Cell. 2006 Oct 20;127(2):397-408
references.pmid: 17055439
references.citation: Adv Drug Deliv Rev. 2009 Nov 30;61(14):1369-74
references.pmid: 19716394
references.citation: Can J Neurol Sci. 1976 Nov;3(4):361-4
references.pmid: 1000422
references.citation: Novartis Found Symp. 2007;286:3-6; discusssion 6-12, 162-3, 196-203
references.pmid: 18269170
references.citation: Science. 1997 Jun 13;276(5319):1709-12
references.pmid: 9180083
references.citation: Nucleic Acids Res. 2007;35(16):5351-9
references.pmid: 17693431
references.citation: Neurology. 2000 Dec 12;55(11):1752-3
references.pmid: 11113241
references.citation: Cerebellum. 2009 Jun;8(2):98-103
references.pmid: 19104905
references.citation: Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):438-43
references.pmid: 16677089
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6570-5
references.pmid: 15100410
references.citation: Hum Mol Genet. 2002 Nov 1;11(23):2989-96
references.pmid: 12393810