Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Autophagy-dependent removal of α-synuclein: a novel mechanism of GM1 ganglioside neuroprotection against Parkinson’s disease


GM1 ganglioside is particularly abundant in the mammalian central nervous system and has shown beneficial effects on neurodegenerative diseases. In this study, we investigated the therapeutic effect of GM1 ganglioside in experimental models of Parkinson’s disease (PD) in vivo and in vitro. Mice were injected with MPTP (30 mg·kg-1·d−1, i.p.) for 5 days, resulting in a subacute model of PD. PD mice were treated with GM1 ganglioside (25, 50 mg·kg1·d−1, i.p.) for 2 weeks. We showed that GM1 ganglioside administration substantially improved the MPTP-induced behavioral disturbance and increased the levels of dopamine and its metabolites in the striatal tissues. In the MPP+-treated SH-SY5Y cells and α-synuclein (α-Syn) A53T-overexpressing PC12 (PC12α-Syn A53T) cells, treatment with GM1 ganglioside (40 μM) significantly decreased α-Syn accumulation and alleviated mitochondrial dysfunction and oxidative stress. We further revealed that treatment with GM1 ganglioside promoted autophagy, evidenced by the autophagosomes that appeared in the substantia nigra of PD mice as well as the changes of autophagy-related proteins (LC3-II and p62) in the MPP+-treated SH-SY5Y cells. Cotreatment with the autophagy inhibitor 3-MA or bafilomycin A1 abrogated the in vivo and in vitro neuroprotective effects of GM1 ganglioside. Using GM1 ganglioside labeled with FITC fluorescent, we observed apparent colocalization of GM1-FITC and α-Syn as well as GM1-FITC and LC3 in PC12α-Syn A53T cells. GM1 ganglioside significantly increased the phosphorylation of autophagy regulatory proteins ATG13 and ULK1 in doxycycline-treated PC12α-Syn A53T cells and the MPP+-treated SH-SY5Y cells, which was inhibited by 3-MA. Taken together, this study demonstrates that the anti-PD role of GM1 ganglioside resulted from activation of autophagy-dependent α-Syn clearance.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: GM1 ganglioside treatment improves the progression of disease in MPTP-treated mice.
Fig. 2: GM1 ganglioside has therapeutic potential in the MPP+-treated SH-SY5Y cells.
Fig. 3: GM1 ganglioside activates autophagy in SH-SY5Y cells.
Fig. 4: GM1 ganglioside enhances α-Syn clearance and promotes autophagy in MPP+-treated SH-SY5Y cells.
Fig. 5: GM1 ganglioside increases α-Syn clearance through autophagy and induces the colocalization of α-Syn and LC3 in PC12α-Syn A53T cells.
Fig. 6: Effect of GM1 ganglioside on the phosphorylation of ATG13 and ULK1.


  1. 1.

    Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Prim. 2017;3:21.

    Google Scholar 

  2. 2.

    de Lau LML, Breteler MMB. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525–35.

    PubMed  Google Scholar 

  3. 3.

    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–40.

    CAS  PubMed  Google Scholar 

  4. 4.

    Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjorklund T, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128:805–20.

    PubMed  Google Scholar 

  5. 5.

    Vila M, Vukosavic S, Jackson-Lewis V, Neystat M, Jakowec M, Przedborski S. Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the Parkinsonian toxin MPTP. J Neurochem. 2000;74:721–9.

    CAS  PubMed  Google Scholar 

  6. 6.

    Kalivendi SV, Cunningham S, Kotamraju S, Joseph J, Hillard CJ, Kalyanaraman B. Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide. J Biol Chem. 2004;279:15240–7.

    CAS  PubMed  Google Scholar 

  7. 7.

    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–7.

    CAS  PubMed  Google Scholar 

  8. 8.

    Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet. 1998;18:106–8.

    PubMed  Google Scholar 

  9. 9.

    Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004;55:164–73.

    CAS  PubMed  Google Scholar 

  10. 10.

    Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target alpha-synuclein pathology. Exp Neurol. 2017;298:225–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Björklund A. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc Natl Acad Sci USA. 2013;110:E1817–E1826.

    CAS  PubMed  Google Scholar 

  12. 12.

    Decressac M, Björklund A. TFEB: pathogenic role and therapeutic target in Parkinson disease. Autophagy. 2013;9:1244–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci. 2009;29:13578–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J Neurosci. 2010;30:1166–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Bové J, Martínez-Vicente M, Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci. 2011;12:437–52.

    PubMed  Google Scholar 

  16. 16.

    Macher BA, Sweeley CC. Glycosphingolipids: structure, biological source, and properties. Methods Enzymol. 1978;50:236–51.

    CAS  PubMed  Google Scholar 

  17. 17.

    Lim ST, Esfahani K, Avdoshina V, Mocchetti I. Exogenous gangliosides increase the release of brain-derived neurotrophic factor. Neuropharmacology. 2011;60:1160–7.

    CAS  PubMed  Google Scholar 

  18. 18.

    Furukawa K, Ohmi Y, Ohkawa Y, Tokuda N, Kondo Y, Tajima O, et al. Regulatory mechanisms of nervous systems with glycosphingolipids. Neurochem Res. 2011;36:1578–86.

    CAS  PubMed  Google Scholar 

  19. 19.

    Hadjiconstantinou M, Neff NH. Treatment with GM1 ganglioside restores striatal dopamine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse. J Neurochem. 1988;51:1190–6.

    CAS  PubMed  Google Scholar 

  20. 20.

    Schneider JS, Pope A, Simpson K, Taggart J, Smith MG, DiStefano L. Recovery from experimental parkinsonism in primates with GM1 ganglioside treatment. Science. 1992;256:843–6.

    CAS  PubMed  Google Scholar 

  21. 21.

    Favaron M, Manev H, Alho H, Bertolino M, Ferret B, Guidotti A, et al. Gangliosides prevent glutamate and kainate neurotoxicity in primary neuronal cultures of neonatal rat cerebellum and cortex. Proc Natl Acad Sci USA. 1988;85:7351–5.

    CAS  PubMed  Google Scholar 

  22. 22.

    Sofroniew MV, Pearson RC, Cuello AC, Tagari PC, Stephens PH. Parenterally administered GM1 ganglioside prevents retrograde degeneration of cholinergic cells of the rat basal forebrain. Brain Res. 1986;398:393–6.

    CAS  PubMed  Google Scholar 

  23. 23.

    Schneider JS, Roeltgen DP, Rothblat DS, Chapas-Crilly J, Seraydarian L, Rao J. GM1 ganglioside treatment of Parkinson’s disease: an open pilot study of safety and efficacy. Neurology. 1995;45:1149–54.

    CAS  PubMed  Google Scholar 

  24. 24.

    Schneider JS, Sendek S, Daskalakis C, Cambi F. GM1 ganglioside in Parkinson’s disease: Results of a five year open study. J Neurol Sci. 2010;292:45–51.

    CAS  PubMed  Google Scholar 

  25. 25.

    Schneider JS, Gollomp SM, Sendek S, Colcher A, Cambi F, Du W. A randomized, controlled, delayed start trial of GM1 ganglioside in treated Parkinson’s disease patients. J Neurol Sci. 2013;324:140–8.

    CAS  PubMed  Google Scholar 

  26. 26.

    Schneider JS, Cambi F, Gollomp SM, Kuwabara H, Brašić JR, Leiby B, et al. GM1 ganglioside in Parkinson’s disease: Pilot study of effects on dopamine transporter binding. J Neurol Sci. 2015;356:118–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Agnati LF, Fuxe K, Calza L, Benfenati F, Cavicchioli L, Toffano G, et al. Gangliosides increase the survival of lesioned nigral dopamine neurons and favour the recovery of dopaminergic synaptic function in striatum of rats by collateral sprouting. Acta Physiol Scand. 1983;119:347–63.

    CAS  PubMed  Google Scholar 

  28. 28.

    Hadjiconstantinou M, Mariani AP, Neff NH. GM1 ganglioside-induced recovery of nigrostriatal dopaminergic neurons after MPTP: an immunohistochemical study. Brain Res. 1989;484:297–303.

    CAS  PubMed  Google Scholar 

  29. 29.

    Skaper SD, Leon A, Toffano G. Ganglioside function in the development and repair of the nervous system. From basic science to clinical application. Mol Neurobiol. 1989;3:173–99.

    CAS  PubMed  Google Scholar 

  30. 30.

    Liu J, Wang X, Lu YQ, Duan CL, Gao G, Lu LL, et al. Pink1 interacts with alpha-synuclein and abrogates α-synuclein-induced neurotoxicity by activating autophagy. Cell Death Dis. 2017;8:e3056.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Su M, Shi JJ, Yang YP, Li J, Zhang YL, Chen J, et al. HDAC6 regulates aggresome-autophagy degradation pathway of α-synuclein in response to MPP+-induced stress. J Neurochem. 2011;117:112–20.

    CAS  PubMed  Google Scholar 

  32. 32.

    Chen LL, Song JX, Lu JH, Yuan ZW, Liu LF, Durairajan SSK, et al. Corynoxine, a natural autophagy enhancer, promotes the clearance of alpha-synuclein via Akt/mTOR pathway. J Neuroimmune Pharmacol. 2014;9:380–7.

    PubMed  Google Scholar 

  33. 33.

    Bhangale JO, Acharya SR. Anti-Parkinson activity of petroleum ether extract of ficus religiosa (L.) leaves. Adv Pharmacol Sci. 2016;2016:9436106.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Wang XH, Lu G, Hu X, Tsang KS, Kwong WH, Wu FX, et al. Quantitative assessment of gait and neurochemical correlation in a classical murine model of Parkinson’s disease. BMC Neurosci. 2012;13:142.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Feng GS, Zhang ZJ, Bao QQ, Zhang ZJ, Zhou LB, Jiang J, et al. Protective effect of chinonin in MPTP-induced C57BL/6 mouse model of Parkinson’s disease. Biol Pharm Bull. 2014;37:1301–7.

    CAS  PubMed  Google Scholar 

  36. 36.

    Vila M, Przedborski S. Targeting programmed cell death in neurodegenerative diseases. Nat Rev Neurosci. 2003;4:365–75.

    CAS  PubMed  Google Scholar 

  37. 37.

    Meredith GE, Rademacher DJ. MPTP mouse models of Parkinson’s disease: an update. J Parkinsons Dis. 2011;1:19–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Kim-Han JS, Antenor-Dorsey JA, O’Malley KL. The parkinsonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine axons. J Neurosci. 2011;31:7212–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Zeng XS, Geng WS, Jia JJ. Neurotoxin-induced animal models of Parkinson disease: pathogenic mechanism and assessment. ASN Neuro. 2018;10:1759091418777438.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Martinez TN, Greenamyre JT. Toxin models of mitochondrial dysfunction in Parkinson’s disease. Antioxid Redox Signal. 2012;16:920–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Subramaniam SR, Chesselet MF. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol. 2013;106-107:17–32.

    CAS  PubMed  Google Scholar 

  42. 42.

    Dai RW, Zhang SJ, Duan WJ, Wei RR, Chen HF, Cai WB, et al. Enhanced autophagy contributes to protective effects of GM1 ganglioside against Aβ1-42-induced neurotoxicity and cognitive deficits. Neurochem Res. 2017;42:2417–26.

    CAS  PubMed  Google Scholar 

  43. 43.

    Hwang J, Lee S, Lee JT, Kwon TK, Kim DR, Kim H, et al. Gangliosides induce autophagic cell death in astrocytes. Br J Pharmacol. 2010;159:586–603.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Kasahara R, Yamamoto N, Suzuki K, Sobue K. The σ1 receptor regulates accumulation of GM1 ganglioside-enriched autophagosomes in astrocytes. Neuroscience. 2017;340:176–87.

    CAS  PubMed  Google Scholar 

  45. 45.

    Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest. 2015;125:25–32.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140:313–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Lashuel HA, Overk CR, Oueslati A, Masliah E. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013;14:38–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Ganley IG, Lam DH, Wang JR, Ding XJ, Chen S, Jiang XJ. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009;284:12297–305.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol. 2010;22:132–9.

    CAS  PubMed  Google Scholar 

  50. 50.

    Schneider JS, Aras R, Williams CK, Koprich JB, Brotchie JM, Singh V. GM1 ganglioside modifies α-synuclein toxicity and is neuroprotective in a Rat α-synuclein model of parkinson’s disease. Sci Rep. 2019;9:8362.

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Oertel WH, Quinn NP. Parkinson’s disease: drug therapy. Baillieres Clin Neurol. 1997;6:89–108.

    CAS  PubMed  Google Scholar 

  52. 52.

    Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351:2498–508.

    CAS  PubMed  Google Scholar 

  53. 53.

    PD Med Collaborative Group, Gray R, Ives N, Rick C, Patel S, Gray A, et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised. Lancet. 2014;384:1196–205.

    Google Scholar 

  54. 54.

    Bibbiani F, Oh JD, Chase TN. Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models. Neurology. 2001;57:1829–34.

    CAS  PubMed  Google Scholar 

  55. 55.

    Brotchie JM. Nondopaminergic mechanisms in levodopa-induced dyskinesia. Mov Disord. 2005;20:919–31.

    PubMed  Google Scholar 

  56. 56.

    Fabbrini G, Barbanti P, Aurilia C, Pauletti C, Lenzi GL, Meco G. Donepezil in the treatment of hallucinations and delusions in Parkinson’s disease. Neurol Sci. 2002;23:41–43.

    CAS  PubMed  Google Scholar 

  57. 57.

    Schapira AH, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, et al. Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Disco. 2006;5:845–54.

    CAS  Google Scholar 

  58. 58.

    He Q, Koprich JB, Wang Y, Yu WB, Xiao BG, Brotchie JM, et al. Treatment with trehalose prevents behavioral and neurochemical deficits produced in an AAV α-synuclein rat model of Parkinson’s disease. Mol Neurobiol. 2016;53:2258–68.

    CAS  PubMed  Google Scholar 

  59. 59.

    Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem. 2007;282:5641–52.

    CAS  PubMed  Google Scholar 

  60. 60.

    Lu JH, Tan JQ, Durairajan SS, Liu LF, Zhang ZH, Ma L, et al. Isorhynchophylline, a natural alkaloid, promotes the degradation of alpha-synuclein in neuronal cells via inducing autophagy. Autophagy. 2012;8:98–108.

    CAS  PubMed  Google Scholar 

  61. 61.

    Steele JW, Ju S, Lachenmayer ML, Liken J, Stock A, Kim SH, et al. Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain. Mol Psychiatry. 2013;18:882–8.

    CAS  PubMed  Google Scholar 

  62. 62.

    Hebron ML, Lonskaya I, Moussa CEH. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson’s disease models. Hum Mol Genet. 2013;22:3315–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Takamura A, Higaki K, Kajimaki K, Otsuka S, Ninomiya H, Matsuda J, et al. Enhanced autophagy and mitochondrial aberrations in murine G(M1)-gangliosidosis. Biochem Biophys Res Commun. 2008;367:616–22.

    CAS  PubMed  Google Scholar 

  64. 64.

    Chan EY. Regulation and function of uncoordinated-51 like kinase proteins. Antioxid Redox Signal. 2012;17:775–5.

    CAS  PubMed  Google Scholar 

  65. 65.

    Lin MG, Hurley JH. Structure and function of the ULK1 complex in autophagy. Curr Opin Cell Biol. 2016;39:61–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Wong PM, Puente C, Ganley IG, Jiang XJ. The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy. 2013;9:124–37.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


This work was supported, in part, by the National Key Research and Development Program of China (2017YFC1700400 and 2017YFC1700404), the National Natural Science Foundation of China (81873209, 81903821, 81973718, 81673709, and U1801284), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y036) and GDUPS (2019), the Guangdong Science and Technology Foundation for Distinguished Young Scholars (2017A030306004), the Natural Science Foundation of Guangdong Province (2019A1515010909), and the Science and Technology Program of Guangzhou (201903010062).

Author information




YLG and WJD contributed equally to this work. WJD and RRH designed the project. YLG, DHL, XHM, XXL, and ZL carried out all the experiments. YLG, WJD, DHL, XXL, ZL, WB, and HZL contributed to the statistical analyses and interpretation of the results. YLG and WJD contributed to drafting of the manuscript. WJD, HK, YFL, and RRH revised the paper. All authors edited and agreed to the final version of the manuscript.

Corresponding authors

Correspondence to Hai-Zhi Liu or Yi-Fang Li or Rong-Rong He.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Guo, YL., Duan, WJ., Lu, DH. et al. Autophagy-dependent removal of α-synuclein: a novel mechanism of GM1 ganglioside neuroprotection against Parkinson’s disease. Acta Pharmacol Sin 42, 518–528 (2021).

Download citation


  • Parkinson’s disease
  • GM1 ganglioside
  • α-synuclein
  • autophagy
  • dopamine

Further reading


Quick links