Skip to main content
SpringerLink
Log in

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

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Ahmad B, Lapidus LJ (2012) Curcumin prevents aggregation in α-synuclein by increasing reconfiguration rate. J Biol Chem 287:9193–9199

    Article  PubMed  CAS  Google Scholar 

  • 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 121:161–175

    Article  PubMed  CAS  Google Scholar 

  • 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 72:29–39

    Article  PubMed  CAS  Google Scholar 

  • 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 18:2893–2904

    Article  PubMed  CAS  Google Scholar 

  • 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 29:3365–3373

    Article  PubMed  CAS  Google Scholar 

  • 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:e9313

    Article  PubMed  Google Scholar 

  • Dauer W, Przedborski S (2003) Parkinson’s disease mechanisms and models. Neuron 39:889–909

    Article  PubMed  CAS  Google Scholar 

  • Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822

    Article  PubMed  CAS  Google Scholar 

  • 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 33:2841–2854

    Google Scholar 

  • 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 670:29–38

    Article  PubMed  CAS  Google Scholar 

  • Hsu CH, Cheng AL (2007) Clinical studies with curcumin. Adv Exp Med Biol 595:471–480

    Article  PubMed  Google Scholar 

  • 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 2012

  • 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 19:5720–5728

    Article  PubMed  CAS  Google Scholar 

  • 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 283:6979–6987

    Article  PubMed  CAS  Google Scholar 

  • 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):1018–1025

    Article  PubMed  CAS  Google Scholar 

  • Klionsky DJ, Abeliovich H, Agostinis P et al (2008) Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4:151–175

    PubMed  CAS  Google Scholar 

  • Kroemer G, Mariño G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40:280–293

    Article  PubMed  CAS  Google Scholar 

  • 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 18:106–108

    Article  PubMed  Google Scholar 

  • 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 37:2025–2032

    Article  PubMed  CAS  Google Scholar 

  • 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 40:11604–11613

    Article  PubMed  CAS  Google Scholar 

  • 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 21:8370–8377

    PubMed  CAS  Google Scholar 

  • 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 63:439–444

    Article  PubMed  Google Scholar 

  • 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 8:98–108

    Article  PubMed  CAS  Google Scholar 

  • Mansouri Z, Sabetkasaei M, Moradi F, Masoudnia F, Ataie A (2012) Curcumin has neuroprotection effect on homocysteine rat model of parkinson. J Mol Neurosci 47:234–242

    Article  PubMed  CAS  Google Scholar 

  • Marino G, Lopez-Otin C (2004) Autophagy: molecular mechanisms, physiological functions and relevance in human pathology. Cell Mol Life Sci 61:1439–1454

    Article  PubMed  CAS  Google Scholar 

  • 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 68:7283–7292

    Article  PubMed  CAS  Google Scholar 

  • Mizushima N (2010) The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22:132–139

    Article  PubMed  CAS  Google Scholar 

  • Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075

    Article  PubMed  CAS  Google Scholar 

  • Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87

    Article  PubMed  CAS  Google Scholar 

  • 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 1:16–33

    Article  PubMed  CAS  Google Scholar 

  • 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 287:27567–27579

    Article  PubMed  CAS  Google Scholar 

  • Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    Article  PubMed  CAS  Google Scholar 

  • 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 22:1225–1231

    Article  PubMed  CAS  Google Scholar 

  • 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:e13481

    Article  PubMed  Google Scholar 

  • 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:e6

    Article  PubMed  Google Scholar 

  • 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 47:256–266

    Article  PubMed  CAS  Google Scholar 

  • 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 81:3142–3150

    Article  PubMed  CAS  Google Scholar 

  • 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 29:13578–13588

    Article  PubMed  CAS  Google Scholar 

  • Wang MS, Boddapati S, Emadi S, Sierks MR (2010a) Curcumin reduces α-synuclein induced cytotoxicity in Parkinson’s disease cell model. BMC Neurosci 11:57–66

    Article  PubMed  Google Scholar 

  • 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 20:1189–1199

    PubMed  CAS  Google Scholar 

  • Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013

    Article  PubMed  CAS  Google Scholar 

  • Winslow AR, Chen CW, Corrochano S et al (2010) α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol 190:1023–1037

    Article  PubMed  CAS  Google Scholar 

  • Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P (2012) Autophagy: for better or for worse. Cell Res 22:43–61

    Article  PubMed  CAS  Google Scholar 

  • Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22:124–131

    Article  PubMed  CAS  Google Scholar 

  • 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 280:5892–5901

    Article  PubMed  CAS  Google Scholar 

  • 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 26:85–90

    Article  PubMed  Google Scholar 

  • 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 55:164–173

    Article  PubMed  CAS  Google Scholar 

  • 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 19:533–542

    Article  PubMed  CAS  Google Scholar 

  • 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

  • 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 103:684–690

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Neurology & Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China

    Tian-Fang Jiang, Hai-Yan Zhou, Hong-Mei Wang, Li-Peng Tian, Jun Liu, Jian-Qing Ding & Sheng-Di Chen

  2. Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Science & Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China

    Ying-Jie Zhang & Sheng-Di Chen

Authors
  1. Tian-Fang Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying-Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hai-Yan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong-Mei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li-Peng Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian-Qing Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sheng-Di Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sheng-Di Chen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(JPEG 57 kb)

High resolution image (TIFF 3061 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jiang, TF., Zhang, YJ., Zhou, HY. et al. 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. J Neuroimmune Pharmacol 8, 356–369 (2013). https://doi.org/10.1007/s11481-012-9431-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-012-9431-7

Keywords

Search

Navigation