Vol. 19, No. 3, 2011
Issue release date: August 2011
Free Access
Neurosignals 2011;19:163–174
(DOI:10.1159/000328516)
Original Paper
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Resveratrol-Activated AMPK/SIRT1/Autophagy in Cellular Models of Parkinson’s Disease

Wu Y.a–c · Li X.d · Zhu J.X.b · Xie W.b · Le W.b · Fan Z.d · Jankovic J.b, c · Pan T.b, e
aDepartment of Neurology, Shanghai First People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; bDepartment of Neurology, Parkinson’s Disease Research Laboratory, cDepartment of Neurology, Parkinson’s Disease Center and Movement Disorder Clinic, Baylor College of Medicine, and dDepartment of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, Tex., and eDiana Helis Henry Medical Research Foundation, New Orleans, La., USA
email Corresponding Author


 goto top of outline Key Words

  • AMPK
  • Autophagy
  • Parkinson’s disease
  • Resveratrol
  • SIRT1

 goto top of outline Abstract

Excessive misfolded proteins and/or dysfunctional mitochondria, which may cause energy deficiency, have been implicated in the etiopathogenesis of Parkinson’s disease (PD). Enhanced clearance of misfolded proteins or injured mitochondria via autophagy has been reported to have neuroprotective roles in PD models. The fact that resveratrol is a known compound with multiple beneficial effects similar to those associated with energy metabolism led us to explore whether neuroprotective effects of resveratrol are related to its role in autophagy regulation. We tested whether modulation of mammalian silent information regulator 2 (SIRT1) and/or metabolic energy sensor AMP-activated protein kinase (AMPK) are involved in autophagy induction by resveratrol, leading to neuronal survival. Our results showed that resveratrol protected against rotenone-induced apoptosis in SH-SY5Y cells and enhanced degradation of α-synucleins in α-synuclein-expressing PC12 cell lines via autophagy induction. We found that suppression of AMPK and/or SIRT1 caused decrease of protein level of LC3-II, indicating that AMPK and/or SIRT1 are required in resveratrol-mediated autophagy induction. Moreover, suppression of AMPK caused inhibition of SIRT1 activity and attenuated protective effects of resveratrol on rotenone-induced apoptosis, further suggesting that AMPK-SIRT1-autophagy pathway plays an important role in the neuroprotection by resveratrol on PD cellular models.

Copyright © 2011 S. Karger AG, Basel


 goto top of outline References
  1. Kopin IJ, Markey SP: MPTP toxicity, implications for research in Parkinson’s disease. Annu Rev Neurosci 1988;11:81–96.
  2. Sherer TB, Betarberbet R, Tasta CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT: Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci 2003;23:10756–10764.
  3. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P: Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299:256–259.
  4. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW: Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 2004;304:1158–1160.
  5. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM: Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 2005;102:16842–16847.
  6. Rubinsztein DC: The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006;443:780–786.
  7. Pan T, Rawal P, Wu Y, Xie W, Jankovic J, Le W: Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience 2009;164:541–551.
  8. Irrcher I, Park DS: Parkinson’s disease, to live or die by autophagy. Sci Signal 2009;2:pe21.

    External Resources

  9. Pan T, Kondo S, Le W, Jankovic J: The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain 2008;131:1969–1978.

    External Resources

  10. Elmore SP, Qian T, Grissom SF, Lemasters JJ: The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J 2001;15:2286–2287.
  11. Levine B: Eating oneself and uninvited guests, autophagy-related pathways in cellular defense. Cell 2005;120:159–162.
  12. Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, Thompson CB: Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 2005;120:237–248.
  13. Li X, Lu Y, Pan T, Fan Z: Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. Autophagy 2010;6:1066–1077.
  14. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K: Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006;441:880–884.
  15. Williams A, Jahreiss L, Sarkar S, Saiki S, Menzies FM, Ravikumar B, Rubinsztein DC: Aggregate-prone proteins are cleared from the cytosol by autophagy, therapeutic implications. Curr Top Dev Biol 2006;76:89–101.
  16. Gorman AM: Neuronal cell death in neurodegenerative diseases, recurring themes around protein handling. J Cell Mol Med 2008;12:2263–2280.
  17. Cheung ZH, Ip NY: The emerging role of autophagy in Parkinson’s disease. Mol Brain 2009;2:29.

    External Resources

  18. Mizushima N, Levine B, Cuervo AM, Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature 2008;451:1069–1075.
  19. McCray BA, Taylor JP: The role of autophagy in age-related neurodegeneration. Neurosignals 2008;16:75–84.
  20. Pervaiz S, Holme AL: Resveratrol: its biologic targets and functional activity. Antioxid Redox Signal 2009;11:2851–2897.
  21. Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni C, Salmona M, Caccia S, Negro A, Forloni G: The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by α-synuclein or amyloid-β (1–42) peptide. J Neurochem 2009;110:1445–1456.
  22. Haigis MC, Guarente LP: Mammalian sirtuins – emerging roles in physiology, aging, and calorie restriction. Genes Dev 2006;20:2913–2921.
  23. Michan S, Sinclair D: Sirtuins in mammals: insights into their biological function. Biochem J 2007;404:1–13.
  24. Hsieh TC, Wu JM: Resveratrol: biological and pharmaceutical properties as anticancer molecule. Biofactors 2010;36:360–369.
  25. Huang C, Ma WY, Goranson A, Dong Z: Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway. Carcinogenesis 1999;20:237–242.
  26. Doré S: Unique properties of polyphenol stilbenes in the brain: more than direct antioxidant actions; gene/protein regulatory activity. Neurosignals 2005;14:61–70.
  27. De la Lastra CA, Villegas I: Resveratrol as an anti-inflammatory and anti-aging agent, mechanisms and clinical implications. Mol Nutr Food Res 2005;49:405–430.
  28. Shakibaei M, Harikumar KB, Aggarwal BB: Resveratrol addiction, to die or not to die. Mol Nutr Food Res 2009;53:115–128.
  29. Zhang Z, Lowry SF, Guarente L, Haimovich B: Roles of Sirt1 in the acute and restorative phases following induction of inflammation. J Biol Chem 2010;285:41391–41401.
  30. Lee MK, Kang SJ, Poncz M, Song KJ, Park KS: Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine. Exp Mol Med 2007;39:376–384.
  31. Jin F, Wu Q, Lu YF, Gong QH, Shi JS: Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats. Eur J Pharmacol 2008;600:78–82.
  32. Blanchet J, Longpré F, Bureau G, Morissette M, DiPaolo T, Bronchti G, Martinoli MG: Resveratrol, a red wine polyphenol, protects dopaminergic neurons in MPTP-treated mice. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1243–1250.
  33. Lu KT, Ko MC, Chen BY, Huang JC, Hsieh CW, Lee MC, Chiou RY, Wung BS, Peng CH, Yang YL: Neuroprotective effects of resveratrol on MPTP-induced neuron loss mediated by free radical scavenging. J Agric Food Chem 2008;56:6910–6913.
  34. Pallàs M, Casadesús G, Smith MA, Coto-Montes A, Pelegri C, Vilaplana J, Camins A: Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res 2009;6:70–81.
  35. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T: A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 2008;105:3374–3379.
  36. Poels J, Spasić MR, Callaerts P, Norga KK: Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy. Bioessays 2009;31:944–952.
  37. Hardie DG: AMP-activated/SNF1 protein kinases, conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007;8:774–785.
  38. Vingtdeux V, Chandakkar P, Zhao H, d’Abramo C, Davies P, Marambaud P: Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation. FASEB J 2011;25:219–231.
  39. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC: Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein. J Biol Chem 2007;282:5641–5652.
  40. Sarkar S, Ravikumar B, Rubinsztein DC: Autophagic clearance of aggregate-prone proteins associated with neurodegeneration. Methods Enzymol 2009;453:83–110.
  41. Wu Y, Li X, Xie W, Jankovic J, Le W, Pan T: Neuroprotection of deferoxamine on rotenone-induced injury via accumulation of HIF-1α and induction of autophagy in SH-SY5Y cells. Neurochem Int 2010;57:198–205.
  42. Pan T, Kondo S, Zhu W, Xie W, Jankovic J, Le W: Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol Dis 2008;32:16–25.
  43. Corcelle EA, Puustinen P, Jäättelä M: Apoptosis and autophagy: targeting autophagy signalling in cancer cells – ‘trick or treats’? FEBS J 2009;276:6084–6096.
  44. Puissant A, Robert G, Fenouille N, Luciano F, Cassuto JP, Raynaud S, Auberger P: Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res 2010;70:1042–1052.
  45. Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y: Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct 1998;23:33–42.
  46. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG: Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine-172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 1996;271:27879–27887.
  47. Hardie DG, Carling D, Carlson M: The AMP-activated/SNF1 protein kinase subfamily, metabolic sensors of the eukaryotic cell? Annu Rev Biochem 1998;67:821–855.
  48. Lee M, Hwang JT, Lee HJ, Jung SN, Kang I, Chi SG, Kim SS, Ha J: AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. J Biol Chem 2003;278:39653–29661.
  49. Jung SN, Yang WK, Kim J, Kim HS, Kim EJ, Yun H, Park H, Kim SS, Choe W, Kang I, Ha J: Reactive oxygen species stabilize hypoxia-inducible factor-1α protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. Carcinogenesis 2008;29:713–721.
  50. Mizushima N: Autophagy, process and function. Genes Dev 2007;21:2861–2873.
  51. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D: Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 2004;305:1292–1295.
  52. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC: Alpha-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003;278:25009–25013.
  53. Scarlatti F, Maffei R, Beau I, Codogno P, Ghidoni R: Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. Cell Death Differ 2008;15:1318–1329.
  54. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006;444:337–342.
  55. Dasgupta B, Milbrandt J: Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA 2007;104:7217–7222.
  56. Park CE, Kim MJ, Lee JH, Min BI, Bae H, Choe W, Kim SS, Ha J: Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase. Exp Mol Med 2007;39:222–229.
  57. Wang A, Liu M, Liu X, Dong LQ, Glickman RD, Slaga TJ, Zhou Z, Liu F: Up-regulation of adiponectin by resveratrol: the essential roles of the Akt/FOXO1 and AMPK signaling pathways and DsbA-L. J Biol Chem 2011;286:60–66.
  58. Kwon KJ, Kim HJ, Shin CY, Han SH: Melatonin potentiates the neuroprotective properties of resveratrol against β-amyloid-induced neurodegeneration by modulating AMP-activated protein kinase pathways. J Clin Neurol 2010;6:127–137.

    External Resources

  59. Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J: AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009;458:1056–1060.
  60. Chau MD, Gao J, Yang Q, Wu Z, Gromada J: Fibroblast growth factor-21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1α pathway. Proc Natl Acad Sci USA 2010;107:12553–12558.
  61. Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, Rahman I: Regulation of SIRT1 in cellular functions, role of polyphenols. Arch Biochem Biophys 2010;501:79–90.
  62. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA: Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305:390–392.
  63. Ghosh HS, McBurney M, Robbins PD: SIRT1 negatively regulates the mammalian target of rapamycin. PLoS One 2010;5:e9199.

    External Resources

  64. Filomeni G, Graziani I, De Zio D, Dini L, Centonze D, Rotilio G, Ciriolo MR: Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity, possible implications for Parkinson’s disease. Neurobiol Aging 2010 (doi 10.1016/j.neurobiolaging.2010.05.021).

 goto top of outline Author Contacts

Dr. Tianhong Pan
Parkinson Disease Research Laboratory
Department of Neurology, Baylor College of Medicine
One Baylor Plaza, MS NB302, Houston, TX 77030 (USA)
Tel. +1 713 798 5142, E-Mail tpan@bcm.edu


 goto top of outline Article Information

Received: January 4, 2011
Accepted after revision: April 18, 2011
Published online: July 22, 2011
Number of Print Pages : 12
Number of Figures : 7, Number of Tables : 0, Number of References : 64


 goto top of outline Publication Details

Neurosignals

Vol. 19, No. 3, Year 2011 (Cover Date: August 2011)

Journal Editor: Ip N.Y. (Hong Kong)
ISSN: 1424-862X (Print), eISSN: 1424-8638 (Online)

For additional information: http://www.karger.com/NSG


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