Cellular and Molecular Life Sciences

, Volume 69, Issue 7, pp 1153–1165 | Cite as

Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease

  • Giuseppa Mudò
  • Johanna Mäkelä
  • Valentina Di Liberto
  • Timofey V. Tselykh
  • Melania Olivieri
  • Petteri Piepponen
  • Ove Eriksson
  • Annika Mälkiä
  • Alessandra Bonomo
  • Minna Kairisalo
  • Jose A. Aguirre
  • Laura Korhonen
  • Natale Belluardo
  • Dan Lindholm
Research article

Abstract

Mitochondrial dysfunction and oxidative stress occur in Parkinson’s disease (PD), but little is known about the molecular mechanisms controlling these events. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. We show here that transgenic mice overexpressing PGC-1α in dopaminergic neurons are resistant against cell degeneration induced by the neurotoxin MPTP. The increase in neuronal viability was accompanied by elevated levels of mitochondrial antioxidants SOD2 and Trx2 in the substantia nigra of transgenic mice. PGC-1α overexpression also protected against MPTP-induced striatal loss of dopamine, and mitochondria from PGC-1α transgenic mice showed an increased respiratory control ratio compared with wild-type animals. To modulate PGC-1α, we employed the small molecular compound, resveratrol (RSV) that protected dopaminergic neurons against the MPTP-induced cell degeneration almost to the same extent as after PGC-1α overexpression. As studied in vitro, RSV activated PGC-1α in dopaminergic SN4741 cells via the deacetylase SIRT1, and enhanced PGC- gene transcription with increases in SOD2 and Trx2. Taken together, the results reveal an important function of PGC-1α in dopaminergic neurons to combat oxidative stress and increase neuronal viability. RSV and other compounds acting via SIRT1/PGC-1α may prove useful as neuroprotective agents in PD and possibly in other neurological disorders.

Keywords

PGC-1α RSV SIRT1 MPTP Dopaminergic neurons Parkinson’s disease 

References

  1. 1.
    de Lau LM, Breteler MM (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535PubMedCrossRefGoogle Scholar
  2. 2.
    Gupta A, Dawson VL, Dawson TM (2008) What causes cell death in Parkinson’s disease? Ann Neurol 64(Suppl 2):S3–S15PubMedGoogle Scholar
  3. 3.
    Schapira AH, Agid Y, Barone P, Jenner P, Lemke MR, Poewe W, Rascol O, Reichmann H, Tolosa E (2009) Perspectives on recent advances in the understanding and treatment of Parkinson’s disease. Eur J Neurol 16:1090–1099PubMedCrossRefGoogle Scholar
  4. 4.
    Abou-Sleiman PM, Muqit MM, Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 7:207–219PubMedCrossRefGoogle Scholar
  5. 5.
    Banerjee R, Starkov AA, Beal MF, Thomas B (2009) Mitochondrial dysfunction in the limelight of Parkinson’s disease pathogenesis. Biochim Biophys Acta 1792:651–663PubMedGoogle Scholar
  6. 6.
    Zhou C, Huang Y, Przedborski S (2008) Oxidative stress in Parkinson’s disease: a mechanism of pathogenic and therapeutic significance. Ann N Y Acad Sci 1147:93–104PubMedCrossRefGoogle Scholar
  7. 7.
    St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408PubMedCrossRefGoogle Scholar
  8. 8.
    Feige JN, Auwerx J (2008) Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 20:303–309PubMedCrossRefGoogle Scholar
  9. 9.
    Lu Z, Xu X, Hu X, Fassett J, Zhu G, Tao Y, Li J, Huang Y, Zhang P, Zhao B, Chen Y (2010) PGC-1 alpha regulates expression of myocardial mitochondrial antioxidants and myocardial oxidative stress after chronic systolic overload. Antioxid Redox Signal 13:1011–1022PubMedCrossRefGoogle Scholar
  10. 10.
    Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122PubMedCrossRefGoogle Scholar
  11. 11.
    Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P (2008) Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 582:46–53PubMedCrossRefGoogle Scholar
  12. 12.
    Pirola L, Fröjdö S (2008) Resveratrol: one molecule, many targets. IUBMB Life 60:323–332PubMedCrossRefGoogle Scholar
  13. 13.
    Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506PubMedCrossRefGoogle Scholar
  14. 14.
    Okawara M, Katsuki H, Kurimoto E, Shibata H, Kume T, Akaike A (2007) Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults. Biochem Pharmacol 73:550–560PubMedCrossRefGoogle Scholar
  15. 15.
    Chao J, Yu MS, Ho YS, Wang M, Chang RC (2008) Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity. Free Radic Biol Med 45:1019–1026PubMedCrossRefGoogle Scholar
  16. 16.
    Blanchet J, Longpré F, Bureau G, Morissette M, DiPaolo T, Bronchti G, Martinoli MG (2008) Resveratrol, a red wine polyphenol, protects dopaminergic neurons in MPTP-treated mice. Prog Neuropsychopharmacol Biol Psychiatry 32:1243–1250PubMedCrossRefGoogle Scholar
  17. 17.
    Caroni P (1997) Overexpression of growth-associated proteins in the neurons of adult transgenic mice. J Neurosci Methods 71:3–9PubMedCrossRefGoogle Scholar
  18. 18.
    Trapp T, Korhonen L, Besselmann M, Martinez R, Mercer EA, Lindholm D (2003) Transgenic mice overexpressing XIAP in neurons show better outcome after transient cerebral ischemia. Mol Cell Neurosci 23:302–313PubMedCrossRefGoogle Scholar
  19. 19.
    Aguirre JA, Leo G, Cueto R, Andbjer B, Naylor A, Medhurst AD, Agnati LF, Fuxe K (2008) The novel cyclooxygenase-2 inhibitor GW637185X protects against l-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine toxicity. Neuroreport 19:657–660PubMedCrossRefGoogle Scholar
  20. 20.
    Hong C, Duit S, Jalonen P, Out R, Scheer L, Sorrentino V, Boyadjian R, Rodenburg KW, Foley E, Korhonen L, Lindholm D, Nimpf J, van Berkel TJ, Tontonoz P, Zelcer N (2010) The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2. J Biol Chem 285:19720–19726PubMedCrossRefGoogle Scholar
  21. 21.
    Airavaara M, Mijatovic J, Vihavainen T, Piepponen TP, Saarma M, Ahtee L (2006) In heterozygous GDNF knockout mice the response of striatal dopaminergic system to acute morphine is altered. Synapse 59:321–329PubMedCrossRefGoogle Scholar
  22. 22.
    Speer O, Morkunaite-Haimi S, Liobikas J, Franck M, Hensbo L, Linder MD, Kinnunen PKJ, Wallimann T, Eriksson O (2003) Rapid suppression of mitochondrial permeability transition by methylglyoxal. Role of reversible arginine modification. J Biol Chem 278:34757–34763PubMedCrossRefGoogle Scholar
  23. 23.
    Son JH, Chun HS, Joh TH, Cho S, Conti B, Lee JW (1999) Neuroprotection and neuronal differentiation studies using substantia nigra dopaminergic cells derived from transgenic mouse embryos. J Neurosci 19:10–20PubMedGoogle Scholar
  24. 24.
    Korhonen L, Belluardo N, Lindholm D (2001) Regulation of X-chromosome-linked inhibitor of apoptosis protein in kainic acid-induced neuronal death in the rat hippocampus. Mol Cell Neurosci 17:364–372PubMedCrossRefGoogle Scholar
  25. 25.
    Sokka AL, Putkonen N, Mudo G, Pryazhnikov E, Reijonen S, Khiroug L, Belluardo N, Lindholm D, Korhonen L (2007) Endoplasmic reticulum stress inhibition protects against excitotoxic neuronal injury in the rat brain. J Neurosci 27:901–908PubMedCrossRefGoogle Scholar
  26. 26.
    Kairisalo M, Korhonen L, Sepp M, Pruunsild P, Kukkonen JP, Kivinen J, Timmusk T, Blomgren K, Lindholm D (2009) NF-kappaB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein. Eur J Neurosci 30:958–966PubMedCrossRefGoogle Scholar
  27. 27.
    Reijonen S, Kukkonen JP, Hyrskyluoto A, Kivinen J, Kairisalo M, Takei N, Lindholm D, Korhonen L (2010) Downregulation of NF-kappaB signaling by mutant huntingtin proteins induces oxidative stress and cell death. Cell Mol Life Sci 67:1929–1941PubMedCrossRefGoogle Scholar
  28. 28.
    Kairisalo M, Korhonen L, Blomgren K, Lindholm D (2007) X-linked inhibitor of apoptosis protein increases mitochondrial antioxidants through NF-kappaB activation. Biochem Biophys Res Commun 364:138–144PubMedCrossRefGoogle Scholar
  29. 29.
    Thomas B, Beal MF (2007) Parkinson’s disease. Hum Mol Genet 16(Spec No. 2):R183–R194PubMedCrossRefGoogle Scholar
  30. 30.
    Heikkila RE, Cabbat FS, Manzino L, Duvoisin RC (1984) Effects of 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine on neostriatal dopamine in mice. Neuropharmacology 23:711–713PubMedCrossRefGoogle Scholar
  31. 31.
    Wang X, Zhu C, Wang X, Hagberg H, Korhonen L, Sandberg M, Lindholm D, Blomgren K (2004) X-linked inhibitor of apoptosis protein (XIAP) protects against caspase activation and tissue loss after neonatal hypoxia-ischemia. Neurobiol Dis 16:179–189PubMedCrossRefGoogle Scholar
  32. 32.
    Wootz H, Hansson I, Korhonen L, Lindholm D (2006) XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice. Exp Cell Res 312(10):1890–1898PubMedCrossRefGoogle Scholar
  33. 33.
    Zhu C, Xu F, Fukuda A, Wang X, Fukuda H, Korhonen L, Hagberg H, Lannering B, Nilsson M, Eriksson PS, Northington FJ, Björk-Eriksson T, Lindholm D, Blomgren K (2007) X-chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants. Eur J Neurosci 26:3402–3410PubMedCrossRefGoogle Scholar
  34. 34.
    Wareski P, Vaarmann A, Choubey V, Safiulina D, Liiv J, Kuum M, Kaasik A (2009) PGC-1α and PGC-1β regulate mitochondrial density in neurons. J Biol Chem 284:21379–21385PubMedCrossRefGoogle Scholar
  35. 35.
    Cowell RM, Blake KR, Russell JW (2007) Localization of the transcriptional coactivator PGC-1alpha to GABAergic neurons during maturation of the rat brain. J Comp Neurol 502:1–18PubMedCrossRefGoogle Scholar
  36. 36.
    Kairisalo M, Bonomo A, Hyrskyluoto A, Mudò G, Belluardo N, Korhonen L, Lindholm D (2011) Resveratrol reduces oxidative stress and cell death and increases mitochondrial antioxidants and XIAP in PC6.3-cells. Neurosci Lett 488:263–266PubMedCrossRefGoogle Scholar
  37. 37.
    Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 281:21745–21754PubMedCrossRefGoogle Scholar
  38. 38.
    Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179PubMedCrossRefGoogle Scholar
  39. 39.
    Dasgupta B, Milbrandt J (2007) Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA 104:7217–7222PubMedCrossRefGoogle Scholar
  40. 40.
    Della-Morte D, Dave KR, DeFazio RA, Bao YC, Raval AP, Perez-Pinzon MA (2009) Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience 159:993–1002PubMedCrossRefGoogle Scholar
  41. 41.
    Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Sener M, Kocak A, Yologlu S (2007) Neuroprotection by resveratrol against traumatic brain injury in rats. Mol Cell Biochem 294:137–144PubMedCrossRefGoogle Scholar
  42. 42.
    Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC (2002) Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson’s disease. J Neurochem 82:615–624PubMedCrossRefGoogle Scholar
  43. 43.
    Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB (2004) Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 88:494–501PubMedCrossRefGoogle Scholar
  44. 44.
    Schintu N, Frau L, Ibba M, Caboni P, Garau A, Carboni E, Carta AR (2009) PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson’s disease. Eur J Neurosci 29:954–963PubMedCrossRefGoogle Scholar
  45. 45.
    Zheng B et al (2010) PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Science Transl Med 2(52):52ra73CrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Giuseppa Mudò
    • 1
  • Johanna Mäkelä
    • 2
  • Valentina Di Liberto
    • 1
  • Timofey V. Tselykh
    • 2
    • 3
  • Melania Olivieri
    • 1
  • Petteri Piepponen
    • 4
  • Ove Eriksson
    • 2
    • 5
  • Annika Mälkiä
    • 3
  • Alessandra Bonomo
    • 1
  • Minna Kairisalo
    • 3
  • Jose A. Aguirre
    • 6
  • Laura Korhonen
    • 2
    • 3
  • Natale Belluardo
    • 1
  • Dan Lindholm
    • 2
    • 3
  1. 1.Department of Experimental Biomedicine and Clinical Neuroscience, Division of Human PhysiologyUniversity of PalermoPalermoItaly
  2. 2.Institute of Biomedicine, Biochemistry and Developmental BiologyUniversity of HelsinkiHelsinkiFinland
  3. 3.Minerva Medical Research InstituteHelsinkiFinland
  4. 4.Faculty of Pharmacy, Division of Pharmacology and ToxicologyUniversity of HelsinkiHelsinkiFinland
  5. 5.Research Program Unit, Biomedicum HelsinkiUniversity of HelsinkiHelsinkiFinland
  6. 6.Department of Human PhysiologySchool of Medicine, University of MalagaMalagaSpain

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