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

Authors: Yu-Lin Guo1,2, Wen-Jun Duan1,2, Dan-Hua Lu1,2, Xiao-Hui Ma1,2, Xiao-Xiao Li1,2, Zhao Li1,2, Wei Bi3, Hiroshi Kurihara1,2, Hai-Zhi Liu3, Yi-Fang Li1,2, Rong-Rong He1,2,4
1 Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou 510632, China
2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China
3 The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
4 Integrated Chinese and Western Medicine Department, School of Chinese Medicine, Jinan University, Guangzhou 510632, China
Correspondence to: Hai-Zhi Liu: gzzzh2011@126.com, Yi-Fang Li: liyifang706@jnu.edu.cn, Rong-Rong He: rongronghe@jnu.edu.cn,
DOI: 10.1038/s41401-020-0454-y
Received: 16 March 2020
Accepted: 1 June 2020
Advance online: 28 July 2020

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.
Keywords: Parkinson’s disease; GM1 ganglioside; α-synuclein; autophagy; dopamine

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