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·kg−1·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.
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Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Prim. 2017;3:21.
de Lau LML, Breteler MMB. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525–35.
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–40.
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.
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.
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.
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.
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.
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.
Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target alpha-synuclein pathology. Exp Neurol. 2017;298:225–35.
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.
Decressac M, Björklund A. TFEB: pathogenic role and therapeutic target in Parkinson disease. Autophagy. 2013;9:1244–6.
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.
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.
Bové J, Martínez-Vicente M, Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci. 2011;12:437–52.
Macher BA, Sweeley CC. Glycosphingolipids: structure, biological source, and properties. Methods Enzymol. 1978;50:236–51.
Lim ST, Esfahani K, Avdoshina V, Mocchetti I. Exogenous gangliosides increase the release of brain-derived neurotrophic factor. Neuropharmacology. 2011;60:1160–7.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Bhangale JO, Acharya SR. Anti-Parkinson activity of petroleum ether extract of ficus religiosa (L.) leaves. Adv Pharmacol Sci. 2016;2016:9436106.
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.
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.
Vila M, Przedborski S. Targeting programmed cell death in neurodegenerative diseases. Nat Rev Neurosci. 2003;4:365–75.
Meredith GE, Rademacher DJ. MPTP mouse models of Parkinson’s disease: an update. J Parkinsons Dis. 2011;1:19–33.
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.
Zeng XS, Geng WS, Jia JJ. Neurotoxin-induced animal models of Parkinson disease: pathogenic mechanism and assessment. ASN Neuro. 2018;10:1759091418777438.
Martinez TN, Greenamyre JT. Toxin models of mitochondrial dysfunction in Parkinson’s disease. Antioxid Redox Signal. 2012;16:920–34.
Subramaniam SR, Chesselet MF. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol. 2013;106-107:17–32.
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.
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.
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.
Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest. 2015;125:25–32.
Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140:313–26.
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.
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.
Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol. 2010;22:132–9.
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.
Oertel WH, Quinn NP. Parkinson’s disease: drug therapy. Baillieres Clin Neurol. 1997;6:89–108.
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.
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.
Bibbiani F, Oh JD, Chase TN. Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models. Neurology. 2001;57:1829–34.
Brotchie JM. Nondopaminergic mechanisms in levodopa-induced dyskinesia. Mov Disord. 2005;20:919–31.
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.
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.
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.
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.
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.
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.
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.
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.
Chan EY. Regulation and function of uncoordinated-51 like kinase proteins. Antioxid Redox Signal. 2012;17:775–5.
Lin MG, Hurley JH. Structure and function of the ULK1 complex in autophagy. Curr Opin Cell Biol. 2016;39:61–8.
Wong PM, Puente C, Ganley IG, Jiang XJ. The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy. 2013;9:124–37.
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).
The authors declare no competing interests.
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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). https://doi.org/10.1038/s41401-020-0454-y
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