Advertisement

Journal of Neuroimmune Pharmacology

, Volume 8, Issue 1, pp 356–369 | Cite as

Curcumin Ameliorates the Neurodegenerative Pathology in A53T α-synuclein Cell Model of Parkinson’s Disease Through the Downregulation of mTOR/p70S6K Signaling and the Recovery of Macroautophagy

  • Tian-Fang Jiang
  • Ying-Jie Zhang
  • Hai-Yan Zhou
  • Hong-Mei Wang
  • Li-Peng Tian
  • Jun Liu
  • Jian-Qing Ding
  • Sheng-Di ChenEmail author
ORIGINAL ARTICLE

Abstract

Parkinson’s disease (PD) is pathologically characterized by the presence of α-synuclein positive intracytoplasmic inclusions. The missense mutation, A53T α-synuclein is closely related to hereditary, early-onset PD. Accumulating evidences suggest that pathological accumulation of A53T α-synuclein protein will perturb itself to be efficiently and normally degraded through its usual degradation pathway, macroautophagy-lysosome pathway, therefore toxic effects on the neuron will be exacerbated. Based on the above fact, we demonstrated in this study that A53T α-synuclein overexpression impairs macroautophagy in SH-SY5Y cells and upregulates mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) signaling, the classical suppressive pathway of autophagy. We further found that curcumin, a natural compound derived from the curry spice turmeric and with low toxicity in normal cells, could efficiently reduce the accumulation of A53T α-synuclein through downregulation of the mTOR/p70S6K signaling and recovery of macroautophagy which was suppressed. These findings suggested that the regulation of mTOR/p70S6K signaling may be a participant of the accumulation of A53T α-synuclein protein-linked Parkinsonism. Meanwhile curcumin could be a candidate neuroprotective agent by inducing macroautophagy, and needs to be further investigated by clinical application in patients suffering Parkinson’s disease.

Keywords

Parkinson’s disease α-synuclein Curcumin Autophagy mTOR/p70S6K signaling 

Notes

Acknowledgments

This work was granted by the National Program of Basic Research of China (2010CB945200, 2011CB504104), the Natural Science Fund (30872729, 30971031, 81129018), Shanghai Key Project of Basic Science Research (10411954500), and Program for Outstanding Medical Academic Leader (LJ 06003). We would like to thank Prof. T. Yoshimori (Osaka University) and Prof. N. Mizushima (Tokyo metropolitan medical science research institute) for the generous gift of the LC3 cDNA.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11481_2012_9431_Fig8_ESM.jpg (58 kb)
ESM 1

(JPEG 57 kb)

11481_2012_9431_MOESM1_ESM.tif (3 mb)
High resolution image (TIFF 3061 kb)

References

  1. Ahmad B, Lapidus LJ (2012) Curcumin prevents aggregation in α-synuclein by increasing reconfiguration rate. J Biol Chem 287:9193–9199PubMedCrossRefGoogle Scholar
  2. Ahsan H, Parveen N, Khan NU, Hadi SM (1999) Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. Chem Biol Interact 121:161–175PubMedCrossRefGoogle Scholar
  3. Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y (2007) Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol 72:29–39PubMedCrossRefGoogle Scholar
  4. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–2904PubMedCrossRefGoogle Scholar
  5. Chung CY, Koprich JB, Siddiqi H, Isacson O (2009) Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. J Neurosci 29:3365–3373PubMedCrossRefGoogle Scholar
  6. Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E, Hansen L, Adame A, Galasko D, Masliah E (2010) Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One 5:e9313PubMedCrossRefGoogle Scholar
  7. Dauer W, Przedborski S (2003) Parkinson’s disease mechanisms and models. Neuron 39:889–909PubMedCrossRefGoogle Scholar
  8. Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822PubMedCrossRefGoogle Scholar
  9. Gui YX, Wang XY, Kang WY, Zhang YJ, Zhang Y, Zhou Y, Quinn TJ, Liu J, Chen SD (2012) Extracellular signal-regulated kinase is involved in alpha-synuclein-induced mitochondrial dynamic disorders by regulating dynamin-like protein 1. Neurobiol Aging 33:2841–2854Google Scholar
  10. Hao J, Pei Y, Ji G, Li W, Feng S, Qiu S (2011) Autophagy is induced by 3β-O-succinyl-lupeol (LD9-4) in A549 cells via up-regulation of Beclin 1 and down-regulation mTOR pathway. Eur J Pharmacol 670:29–38PubMedCrossRefGoogle Scholar
  11. Hsu CH, Cheng AL (2007) Clinical studies with curcumin. Adv Exp Med Biol 595:471–480PubMedCrossRefGoogle Scholar
  12. Hung CS, Liu HH, Huang MT, Cheng CW, Kuo LJ, Ho YS, Wu CH, Chen CM, Wei PL, Chang YJ (2012) Knockdown survivin expression reduces the efficacy of curcumin treatment in hepatocellular carcinoma cells. Ann Surg Oncol. Accessed 19 Jun 2012Google Scholar
  13. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19:5720–5728PubMedCrossRefGoogle Scholar
  14. Kawahara K, Hashimoto M, Bar-On P, Ho GJ, Crews L, Mizuno H, Rockenstein E, Imam SZ, Masliah E (2008) alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease. J Biol Chem 283:6979–6987PubMedCrossRefGoogle Scholar
  15. Kim JY, Cho TJ, Woo BH, Choi KU, Lee CH, Ryu MH, Park HR (2012) Curcumin-induced autophagy contributes to the decreased survival of oral cancer cells. Arch Oral Biol 57(8):1018–1025PubMedCrossRefGoogle Scholar
  16. Klionsky DJ, Abeliovich H, Agostinis P et al (2008) Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4:151–175PubMedGoogle Scholar
  17. Kroemer G, Mariño G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40:280–293PubMedCrossRefGoogle Scholar
  18. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108PubMedCrossRefGoogle Scholar
  19. Lan DM, Liu FT, Zhao J, Chen Y, Wu JJ, Ding ZT, Yue ZY, Ren HM, Jiang YP, Wang J (2012) Effect of Trehalose on PC12 cells overexpressing wild-type or A53T mutant α-synuclein. Neurochem Res 37:2025–2032PubMedCrossRefGoogle Scholar
  20. Li J, Uversky VN, Fink AL (2001) Effect of familial Parkinson’s disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. Biochemistry 40:11604–11613PubMedCrossRefGoogle Scholar
  21. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM (2001) The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21:8370–8377PubMedGoogle Scholar
  22. Liu Z, Yu Y, Li X, Ross CA, Smith WW (2011) Curcumin protects against A53T alpha-synuclein-induced toxicity in a PC12 inducible cell model for Parkinsonism. Pharmacol Res 63:439–444PubMedCrossRefGoogle Scholar
  23. Lu JH, Tan JQ, Durairajan SS, Liu LF, Zhang ZH, Ma L, Shen HM, Chan HY, Li M (2012) Isorhynchophylline, a natural alkaloid, promotes the degradation of alpha-synuclein in neuronal cells via inducing autophagy. Autophagy 8:98–108PubMedCrossRefGoogle Scholar
  24. Mansouri Z, Sabetkasaei M, Moradi F, Masoudnia F, Ataie A (2012) Curcumin has neuroprotection effect on homocysteine rat model of parkinson. J Mol Neurosci 47:234–242PubMedCrossRefGoogle Scholar
  25. Marino G, Lopez-Otin C (2004) Autophagy: molecular mechanisms, physiological functions and relevance in human pathology. Cell Mol Life Sci 61:1439–1454PubMedCrossRefGoogle Scholar
  26. Milacic V, Banerjee S, Landis-Piwowar KR, Sarkar FH, Majumdar AP, Dou QP (2008) Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo. Cancer Res 68:7283–7292PubMedCrossRefGoogle Scholar
  27. Mizushima N (2010) The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22:132–139PubMedCrossRefGoogle Scholar
  28. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075PubMedCrossRefGoogle Scholar
  29. Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87PubMedCrossRefGoogle Scholar
  30. Pan J, Li H, Ma JF, Tan YY, Xiao Q, Ding JQ, Chen SD (2012) Curcumin inhibition of JNKs prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease through suppressing mitochondria dysfunction. Translational Neurodegeneration 1:16–33PubMedCrossRefGoogle Scholar
  31. Petroi D, Popova B, Taheri-Talesh N et al (2012) Aggregate clearance of α-Synuclein in Saccharomyces cerevisiae depends more on Autophagosome and vacuole function than on the proteasome. J Biol Chem 287:27567–27579PubMedCrossRefGoogle Scholar
  32. Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
  33. Quiles JL, Mesa MD, Ramírez-Tortosa CL, Aguilera CM, Battino M, Gil A, Ramírez-Tortosa MC (2002) Curcuma longa extract supplementation reduces oxidative stress and attenuates aortic fatty streak development in rabbits. Arterioscler Thromb Vasc Biol 22:1225–1231PubMedCrossRefGoogle Scholar
  34. Roodveldt C, Labrador-Garrido A, Gonzalez-Rey E, Fernandez-Montesinos R, Caro M, Lachaud CC, Waudby CA, Delgado M, Dobson CM, Pozo D (2010) Glial innate immunity generated by non-aggregated alpha-synuclein in mouse: differences between wild-type and Parkinson’s Disease-linked mutants. PLoS One 5:e13481PubMedCrossRefGoogle Scholar
  35. Sandal M, Valle F, Tessari I, Mammi S, Bergantino E, Musiani F, Brucale M, Bubacco L, Samorì B (2008) Conformational equilibria in monomeric α-synuclein at the single-molecule level. PLoS Biol 6:e6PubMedCrossRefGoogle Scholar
  36. Schwarz L, Goldbaum O, Bergmann M, Probst-Cousin S, Richter-Landsberg C (2012) Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes. J Mol Neurosci 47:256–266PubMedCrossRefGoogle Scholar
  37. Si X, Wang Y, Wong J, Zhang J, McManus BM, Luo H (2007) Dysregulation of the ubiquitin-proteasome system by curcumin suppresses coxsackievirus B3 replication. J Virol 81:3142–3150PubMedCrossRefGoogle Scholar
  38. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 29:13578–13588PubMedCrossRefGoogle Scholar
  39. Wang MS, Boddapati S, Emadi S, Sierks MR (2010a) Curcumin reduces α-synuclein induced cytotoxicity in Parkinson’s disease cell model. BMC Neurosci 11:57–66PubMedCrossRefGoogle Scholar
  40. Wang HM, Zhao YX, Zhang S, Liu GD, Kang WY, Tang HD, Ding JQ, Chen SD (2010b) PPARγ agonist curcumin reduces the amyloid- β -stimulated inflammatory responses in primary astrocytes. J Alzheimers Dis 20:1189–1199PubMedGoogle Scholar
  41. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013PubMedCrossRefGoogle Scholar
  42. Winslow AR, Chen CW, Corrochano S et al (2010) α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol 190:1023–1037PubMedCrossRefGoogle Scholar
  43. Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P (2012) Autophagy: for better or for worse. Cell Res 22:43–61PubMedCrossRefGoogle Scholar
  44. Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22:124–131PubMedCrossRefGoogle Scholar
  45. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280:5892–5901PubMedCrossRefGoogle Scholar
  46. Yang X, Thomas DP, Zhang X, Culver BW, Alexander BM, Murdoch WJ, Rao MN, Tulis DA, Ren J, Sreejayan N (2006) Curcumin inhibits platelet-derived growth factor-stimulated vascular smooth muscle cell function and injury-induced neointima formation. Arterioscler Thromb Vasc Biol 26:85–90PubMedCrossRefGoogle Scholar
  47. Zarranz JJ, Alegre J, Gómez-Esteban JC et al (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173PubMedCrossRefGoogle Scholar
  48. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong JS, Zhang J (2005) Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19:533–542PubMedCrossRefGoogle Scholar
  49. Zhang X, Chen LX, Ouyang L, Cheng Y, Liu B (2012) Plant natural compounds: targeting pathways of autophagy as anti-cancer therapeutic agents. Cell Prolif. doi: 10.1111/j.1365-2184.2012.00833.x
  50. Zhuang W, Long L, Zheng B, Ji W, Yang N, Zhang Q, Liang Z (2012) Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy. Cancer Sci 103:684–690PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Tian-Fang Jiang
    • 1
  • Ying-Jie Zhang
    • 2
  • Hai-Yan Zhou
    • 1
  • Hong-Mei Wang
    • 1
  • Li-Peng Tian
    • 1
  • Jun Liu
    • 1
  • Jian-Qing Ding
    • 1
  • Sheng-Di Chen
    • 1
    • 2
    Email author
  1. 1.Department of Neurology & Institute of NeurologyRuijin Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
  2. 2.Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes for Biological SciencesChinese Academy of Science & Shanghai Jiaotong University School of MedicineShanghaiChina

Personalised recommendations