PPARγ activation rescues mitochondrial function from inhibition of complex I and loss of PINK1

Experimental Neurology

Volumn 253, Issue , 2014, Pages 16-27

  Corona, Juan Carlos ^a,b   de Souza, Senio Campos ^a   Duchen, Michael R ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b HOSPITAL INFANTIL DE MÉXICO FEDERICO GÓMEZ   (Mexico)

Author keywords

Autophagy; Cell death; Mitochondrial biogenesis; Oxidative stress; PINK1; Rotenone

Indexed keywords

PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHOSPHOTRANSFERASE; PTEN INDUCED KINASE 1; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE (UBIQUINONE); ROSIGLITAZONE; ROTENONE; UNCLASSIFIED DRUG;

ARTICLE; AUTOPHAGY; CELL DIFFERENTIATION; CELL FUNCTION; CONTROLLED STUDY; DRUG EFFECT; DRUG MECHANISM; ENZYME ACTIVITY; ENZYME ASSAY; ENZYME INHIBITION; ENZYME MECHANISM; HUMAN; HUMAN CELL; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; MOLECULAR DYNAMICS; MOLECULAR WEIGHT; OXYGEN CONSUMPTION; PRIORITY JOURNAL; PROTEIN DETERMINATION; PROTEIN FUNCTION; SIGNAL TRANSDUCTION;

AUTOPHAGY; CELL DEATH; MITOCHONDRIAL BIOGENESIS; OXIDATIVE STRESS; PINK1; ROTENONE;

ADAPTOR PROTEINS, VESICULAR TRANSPORT; AUTOPHAGY; CELL LINE, TUMOR; ENZYME ACTIVATION; ENZYME INHIBITORS; HIGH MOBILITY GROUP PROTEINS; HUMANS; INSECTICIDES; MEMBRANE POTENTIAL, MITOCHONDRIAL; MICROTUBULE-ASSOCIATED PROTEINS; MITOCHONDRIA; NAD(P)H DEHYDROGENASE (QUINONE); NERVE TISSUE PROTEINS; NF-E2-RELATED FACTOR 2; OXYGEN CONSUMPTION; POSITIVE TRANSCRIPTIONAL ELONGATION FACTOR B; PPAR GAMMA; PROTEIN KINASES; PTEN PHOSPHOHYDROLASE; REACTIVE OXYGEN SPECIES; ROTENONE; TRANSFECTION;

EID: 84891915522     PISSN: 00144886     EISSN: 10902430     Source Type: Journal    
DOI: 10.1016/j.expneurol.2013.12.012     Document Type: Article

References (76)

1. Abdelrahman M., Sivarajah A., Thiemermann C. Beneficial effects of PPAR-gamma ligands in ischemia-reperfusion injury, inflammation and shock. Cardiovasc. Res. 2005, 65:772-781.
2. Alam M., Schmidt W.J. Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav. Brain Res. 2002, 136:317-324.
3. Betarbet R., Sherer T.B., MacKenzie G., Garcia-Osuna M., Panov A.V., Greenamyre J.T. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 2000, 3:1301-1306.
4. Bogacka I., Xie H., Bray G.A., Smith S.R. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 2005, 54:1392-1399.
5. Campanella M., Casswell E., Chong S., Farah Z., Wieckowski M.R., Abramov A.Y., Tinker A., Duchen M.R. Regulation of mitochondrial structure and function by the F1Fo-ATPase inhibitor protein, IF1. Cell Metab. 2008, 8:13-25.
6. Campanella M., Seraphim A., Abeti R., Casswell E., Echave P., Duchen M.R. IF1, the endogenous regulator of the F(1)F(o)-ATPsynthase, defines mitochondrial volume fraction in HeLa cells by regulating autophagy. Biochim. Biophys. Acta 2009, 1787:393-401.
7. Carta A.R., Frau L., Pisanu A., Wardas J., Spiga S., Carboni E. Rosiglitazone decreases peroxisome proliferator receptor-gamma levels in microglia and inhibits TNF-alpha production: new evidences on neuroprotection in a progressive Parkinson's disease model. Neuroscience 2011, 194:250-261.
8. Chaturvedi R.K., Beal M.F. PPAR: a therapeutic target in Parkinson's disease. J. Neurochem. 2008, 106:506-518.
9. Chen Y., McMillan-Ward E., Kong J., Israels S.J., Gibson S.B. Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species. J. Cell Sci. 2007, 120:4155-4166.
10. Chen Y., McMillan-Ward E., Kong J., Israels S.J., Gibson S.B. Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ. 2008, 15:171-182.
11. Chiang M.C., Chern Y., Huang R.N. PPARgamma rescue of the mitochondrial dysfunction in Huntington's disease. Neurobiol. Dis. 2012, 45:322-328.
12. Chung J.H., Seo A.Y., Chung S.W., Kim M.K., Leeuwenburgh C., Yu B.P., Chung H.Y. Molecular mechanism of PPAR in the regulation of age-related inflammation. Ageing Res. Rev. 2008, 7:126-136.
13. Corona J.C., Gimenez-Cassina A., Lim F., Diaz-Nido J. Hexokinase II gene transfer protects against neurodegeneration in the rotenone and MPTP mouse models of Parkinson's disease. J. Neurosci. Res. 2010, 88:1943-1950.
14. Cristiano L., Bernardo A., Ceru M.P. Peroxisome proliferator-activated receptors (PPARs) and peroxisomes in rat cortical and cerebellar astrocytes. J. Neurocytol. 2001, 30:671-683.
15. Cullingford T.E., Bhakoo K., Peuchen S., Dolphin C.T., Patel R., Clark J.B. Distribution of mRNAs encoding the peroxisome proliferator-activated receptor alpha, beta, and gamma and the retinoid X receptor alpha, beta, and gamma in rat central nervous system. J. Neurochem. 1998, 70:1366-1375.
16. Dello Russo C., Gavrilyuk V., Weinberg G., Almeida A., Bolanos J.P., Palmer J., Pelligrino D., Galea E., Feinstein D.L. Peroxisome proliferator-activated receptor gamma thiazolidinedione agonists increase glucose metabolism in astrocytes. J. Biol. Chem. 2003, 278:5828-5836.
17. Frank S., Gaume B., Bergmann-Leitner E.S., Leitner W.W., Robert E.G., Catez F., Smith C.L., Youle R.J. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 2001, 1:515-525.
18. Gandhi S., Wood-Kaczmar A., Yao Z., Plun-Favreau H., Deas E., Klupsch K., Downward J., Latchman D.S., Tabrizi S.J., Wood N.W., Duchen M.R., Abramov A.Y. PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death. Mol. Cell 2009, 33:627-638.
19. Garcia-Bueno B., Caso J.R., Perez-Nievas B.G., Lorenzo P., Leza J.C. Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats. Neuropsychopharmacology 2007, 32:1251-1260.
20. Gautier C.A., Kitada T., Shen J. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:11364-11369.
21. Gegg M.E., Cooper J.M., Schapira A.H., Taanman J.W. Silencing of PINK1 expression affects mitochondrial DNA and oxidative phosphorylation in dopaminergic cells. PLoS One 2009, 4:e4756.
22. Ghosh S., Patel N., Rahn D., McAllister J., Sadeghi S., Horwitz G., Berry D., Wang K.X., Swerdlow R.H. The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. Mol. Pharmacol. 2007, 71:1695-1702.
23. Gispert S., Ricciardi F., Kurz A., Azizov M., Hoepken H.H., Becker D., Voos W., Leuner K., Muller W.E., Kudin A.P., Kunz W.S., Zimmermann A., Roeper J., Wenzel D., Jendrach M., Garcia-Arencibia M., Fernandez-Ruiz J., Huber L., Rohrer H., Barrera M., Reichert A.S., Rub U., Chen A., Nussbaum R.L., Auburger G. Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS One 2009, 4:e5777.
24. Heeman B., Van den Haute C., Aelvoet S.A., Valsecchi F., Rodenburg R.J., Reumers V., Debyser Z., Callewaert G., Koopman W.J., Willems P.H., Baekelandt V. Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance. J. Cell Sci. 2011, 124:1115-1125.
25. Hoepken H.H., Gispert S., Morales B., Wingerter O., Del Turco D., Mulsch A., Nussbaum R.L., Muller K., Drose S., Brandt U., Deller T., Wirth B., Kudin A.P., Kunz W.S., Auburger G. Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiol. Dis. 2007, 25:401-411.
26. Jacobson J., Duchen M.R., Hothersall J., Clark J.B., Heales S.J. Induction of mitochondrial oxidative stress in astrocytes by nitric oxide precedes disruption of energy metabolism. J. Neurochem. 2005, 95:388-395.
27. Jakel R.J., Townsend J.A., Kraft A.D., Johnson J.A. Nrf2-mediated protection against 6-hydroxydopamine. Brain Res. 2007, 1144:192-201.
28. Jung T.W., Lee J.Y., Shim W.S., Kang E.S., Kim S.K., Ahn C.W., Lee H.C., Cha B.S. Rosiglitazone protects human neuroblastoma SH-SY5Y cells against MPP+induced cytotoxicity via inhibition of mitochondrial dysfunction and ROS production. J. Neurol. Sci. 2007, 253:53-60.
29. Langston J.W., Ballard P., Tetrud J.W., Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983, 219:979-980.
30. Lee J.M., Shih A.Y., Murphy T.H., Johnson J.A. NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J. Biol. Chem. 2003, 278:37948-37956.
31. Lehrke M., Lazar M.A. The many faces of PPARgamma. Cell 2005, 123:993-999.
32. Levine B., Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008, 132:27-42.
33. McCoy M.K., Cookson M.R. Mitochondrial quality control and dynamics in Parkinson's disease. Antioxid. Redox Signal. 2012, 16:869-882.
34. McGill J.K., Beal M.F. PGC-1alpha, a new therapeutic target in Huntington's disease?. Cell 2006, 127:465-468.
35. Miglio G., Rosa A.C., Rattazzi L., Collino M., Lombardi G., Fantozzi R. PPARgamma stimulation promotes mitochondrial biogenesis and prevents glucose deprivation-induced neuronal cell loss. Neurochem. Int. 2009, 55:496-504.
36. Moi P., Chan K., Asunis I., Cao A., Kan Y.W. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc. Natl. Acad. Sci. U. S. A. 1994, 91:9926-9930.
37. Moreno S., Farioli-Vecchioli S., Ceru M.P. Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience 2004, 123:131-145.
38. Muqit M.M., Abou-Sleiman P.M., Saurin A.T., Harvey K., Gandhi S., Deas E., Eaton S., Payne Smith M.D., Venner K., Matilla A., Healy D.G., Gilks W.P., Lees A.J., Holton J., Revesz T., Parker P.J., Harvey R.J., Wood N.W., Latchman D.S. Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress. J. Neurochem. 2006, 98:156-169.
39. Narendra D., Tanaka A., Suen D.F., Youle R.J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 2008, 183:795-803.
40. Nolan J.J., Ludvik B., Beerdsen P., Joyce M., Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N. Engl. J. Med. 1994, 331:1188-1193.
41. Osellame L.D., Rahim A.A., Hargreaves I.P., Gegg M.E., Richard-Londt A., Brandner S., Waddington S.N., Schapira A.H., Duchen M.R. Mitochondria and quality control defects in a mouse model of Gaucher disease-links to Parkinson's disease. Cell Metab. 2013, 17:941-953.
42. Panov A., Dikalov S., Shalbuyeva N., Taylor G., Sherer T., Greenamyre J.T. Rotenone model of Parkinson disease: multiple brain mitochondria dysfunctions after short term systemic rotenone intoxication. J. Biol. Chem. 2005, 280:42026-42035.
43. Perez-Ortiz J.M., Tranque P., Vaquero C.F., Domingo B., Molina F., Calvo S., Jordan J., Cena V., Llopis J. Glitazones differentially regulate primary astrocyte and glioma cell survival. Involvement of reactive oxygen species and peroxisome proliferator-activated receptor-gamma. J. Biol. Chem. 2004, 279:8976-8985.
44. Piccoli C., Sardanelli A., Scrima R., Ripoli M., Quarato G., D'Aprile A., Bellomo F., Scacco S., De Michele G., Filla A., Iuso A., Boffoli D., Capitanio N., Papa S. Mitochondrial respiratory dysfunction in familiar parkinsonism associated with PINK1 mutation. Neurochem. Res. 2008, 33:2565-2574.
45. Puigserver P., Spiegelman B.M. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr. Rev. 2003, 24:78-90.
46. Rong J.X., Klein J.L., Qiu Y., Xie M., Johnson J.H., Waters K.M., Zhang V., Kashatus J.A., Remlinger K.S., Bing N., Crosby R.M., Jackson T.K., Witherspoon S.M., Moore J.T., Ryan T.E., Neill S.D., Strum J.C. Rosiglitazone induces mitochondrial biogenesis in differentiated murine 3T3-L1 and C3H/10T1/2 adipocytes. PPAR Res. 2011, 2011:179454.
47. Sato K., Tsuchihara K., Fujii S., Sugiyama M., Goya T., Atomi Y., Ueno T., Ochiai A., Esumi H. Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res. 2007, 67:9677-9684.
48. Schapira A.H., Cooper J.M., Dexter D., Clark J.B., Jenner P., Marsden C.D. Mitochondrial complex I deficiency in Parkinson's disease. J. Neurochem. 1990, 54:823-827.
49. Schintu N., Frau L., Ibba M., Caboni P., Garau A., Carboni E., Carta A.R. PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's disease. Eur. J. Neurosci. 2009, 29:954-963.
50. Schutz B., Reimann J., Dumitrescu-Ozimek L., Kappes-Horn K., Landreth G.E., Schurmann B., Zimmer A., Heneka M.T. The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J. Neurosci. 2005, 25:7805-7812.
51. Shin J.H., Ko H.S., Kang H., Lee Y., Lee Y.I., Pletinkova O., Troconso J.C., Dawson V.L., Dawson T.M. PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease. Cell 2011, 144:689-702.
52. Siebert A., Desai V., Chandrasekaran K., Fiskum G., Jafri M.S. Nrf2 activators provide neuroprotection against 6-hydroxydopamine toxicity in rat organotypic nigrostriatal cocultures. J. Neurosci. Res. 2009, 87:1659-1669.
53. Strum J.C., Shehee R., Virley D., Richardson J., Mattie M., Selley P., Ghosh S., Nock C., Saunders A., Roses A. Rosiglitazone induces mitochondrial biogenesis in mouse brain. J. Alzheimers Dis. 2007, 11:45-51.
54. Takazawa T., Yamauchi T., Tsuchida A., Takata M., Hada Y., Iwabu M., Okada-Iwabu M., Ueki K., Kadowaki T. Peroxisome proliferator-activated receptor gamma agonist rosiglitazone increases expression of very low density lipoprotein receptor gene in adipocytes. J. Biol. Chem. 2009, 284:30049-30057.
55. Tan E.K., Yew K., Chua E., Puvan K., Shen H., Lee E., Puong K.Y., Zhao Y., Pavanni R., Wong M.C., Jamora D., de Silva D., Moe K.T., Woon F.P., Yuen Y., Tan L. PINK1 mutations in sporadic early-onset Parkinson's disease. Mov. Disord. 2006, 21:789-793.
56. Tatsuta T., Langer T. Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J. 2008, 27:306-314.
57. Tontonoz P., Hu E., Spiegelman B.M. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994, 79:1147-1156.
58. Valente E.M., Abou-Sleiman P.M., Caputo V., Muqit M.M., Harvey K., Gispert S., Ali Z., Del Turco D., Bentivoglio A.R., Healy D.G., Albanese A., Nussbaum R., Gonzalez-Maldonado R., Deller T., Salvi S., Cortelli P., Gilks W.P., Latchman D.S., Harvey R.J., Dallapiccola B., Auburger G., Wood N.W. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004, 304:1158-1160.
59. Valente E.M., Salvi S., Ialongo T., Marongiu R., Elia A.E., Caputo V., Romito L., Albanese A., Dallapiccola B., Bentivoglio A.R. PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann. Neurol. 2004, 56:336-341.
60. van Muiswinkel F.L., de Vos R.A., Bol J.G., Andringa G., Jansen Steur E.N., Ross D., Siegel D., Drukarch B. Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiol. Aging 2004, 25:1253-1262.
61. Walker G.E., Marzullo P., Verti B., Guzzaloni G., Maestrini S., Zurleni F., Liuzzi A., Di Blasio A.M. Subcutaneous abdominal adipose tissue subcompartments: potential role in rosiglitazone effects. Obesity (Silver Spring) 2008, 16:1983-1991.
62. Wang B., Williamson G. Detection of a nuclear protein which binds specifically to the antioxidant responsive element (ARE) of the human NAD(P) H:quinone oxidoreductase gene. Biochim. Biophys. Acta 1994, 1219:645-652.
63. Wang Y.L., Frauwirth K.A., Rangwala S.M., Lazar M.A., Thompson C.B. Thiazolidinedione activation of peroxisome proliferator-activated receptor gamma can enhance mitochondrial potential and promote cell survival. J. Biol. Chem. 2002, 277:31781-31788.
64. Wang H.L., Chou A.H., Wu A.S., Chen S.Y., Weng Y.H., Kao Y.C., Yeh T.H., Chu P.J., Lu C.S. PARK6 PINK1 mutants are defective in maintaining mitochondrial membrane potential and inhibiting ROS formation of substantia nigra dopaminergic neurons. Biochim. Biophys. Acta 2011, 1812:674-684.
65. Wang X., Wang Z., Liu J.Z., Hu J.X., Chen H.L., Li W.L., Hai C.X. Double antioxidant activities of rosiglitazone against high glucose-induced oxidative stress in hepatocyte. Toxicol. in Vitro 2011, 25:839-847.
66. Watson G.S., Cholerton B.A., Reger M.A., Baker L.D., Plymate S.R., Asthana S., Fishel M.A., Kulstad J.J., Green P.S., Cook D.G., Kahn S.E., Keeling M.L., Craft S. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am. J. Geriatr. Psychiatry 2005, 13:950-958.
67. Wilson-Fritch L., Burkart A., Bell G., Mendelson K., Leszyk J., Nicoloro S., Czech M., Corvera S. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol. Cell. Biol. 2003, 23:1085-1094.
68. Wilson-Fritch L., Nicoloro S., Chouinard M., Lazar M.A., Chui P.C., Leszyk J., Straubhaar J., Czech M.P., Corvera S. Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J. Clin. Invest. 2004, 114:1281-1289.
69. Wood-Kaczmar A., Gandhi S., Yao Z., Abramov A.Y., Miljan E.A., Keen G., Stanyer L., Hargreaves I., Klupsch K., Deas E., Downward J., Mansfield L., Jat P., Taylor J., Heales S., Duchen M.R., Latchman D., Tabrizi S.J., Wood N.W. PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS One 2008, 3:e2455.
70. Woods J.W., Tanen M., Figueroa D.J., Biswas C., Zycband E., Moller D.E., Austin C.P., Berger J.P. Localization of PPARdelta in murine central nervous system: expression in oligodendrocytes and neurons. Brain Res. 2003, 975:10-21.
71. Wu Z., Puigserver P., Andersson U., Zhang C., Adelmant G., Mootha V., Troy A., Cinti S., Lowell B., Scarpulla R.C., Spiegelman B.M. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999, 98:115-124.
72. Wu J.S., Lin T.N., Wu K.K. Rosiglitazone and PPAR-gamma overexpression protect mitochondrial membrane potential and prevent apoptosis by upregulating anti-apoptotic Bcl-2 family proteins. J. Cell. Physiol. 2009, 220:58-71.
73. Yoo H.Y., Chang M.S., Rho H.M. Induction of the rat Cu/Zn superoxide dismutase gene through the peroxisome proliferator-responsive element by arachidonic acid. Gene 1999, 234:87-91.
74. Yu S.W., Baek S.H., Brennan R.T., Bradley C.J., Park S.K., Lee Y.S., Jun E.J., Lookingland K.J., Kim E.K., Lee H., Goudreau J.L., Kim S.W. Autophagic death of adult hippocampal neural stem cells following insulin withdrawal. Stem Cells 2008, 26:2602-2610.
75. Zhang Q., Hu W., Meng B., Tang T. PPARgamma agonist rosiglitazone is neuroprotective after traumatic spinal cord injury via anti-inflammatory in adult rats. Neurol. Res. 2010, 32:852-859.
76. Zheng B., Liao Z., Locascio J.J., Lesniak K.A., Roderick S.S., Watt M.L., Eklund A.C., Zhang-James Y., Kim P.D., Hauser M.A., Grunblatt E., Moran L.B., Mandel S.A., Riederer P., Miller R.M., Federoff H.J., Wullner U., Papapetropoulos S., Youdim M.B., Cantuti-Castelvetri I., Young A.B., Vance J.M., Davis R.L., Hedreen J.C., Adler C.H., Beach T.G., Graeber M.B., Middleton F.A., Rochet J.C., Scherzer C.R. PGC-1alpha, a potential therapeutic target for early intervention in Parkinson's disease. Sci. Transl. Med. 2010, 2:52ra73.