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

Abstract

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.

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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.

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Acknowledgements

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).

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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.

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

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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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Keywords

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

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