期刊
ACTA PHARMACOLOGICA SINICA
卷 42, 期 4, 页码 518-528出版社
NATURE PUBL GROUP
DOI: 10.1038/s41401-020-0454-y
关键词
Parkinson's disease; GM1 ganglioside; alpha-synuclein; autophagy; dopamine
资金
- National Key Research and Development Program of China [2017YFC1700400, 2017YFC1700404]
- National Natural Science Foundation of China [81873209, 81903821, 81973718, 81673709, U1801284]
- Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program [2017BT01Y036]
- GDUPS (2019)
- Guangdong Science and Technology Foundation for Distinguished Young Scholars [2017A030306004]
- Natural Science Foundation of Guangdong Province [2019A1515010909]
- Science and Technology Program of Guangzhou [201903010062]
GM1 ganglioside has therapeutic effects in experimental models of Parkinson's disease by promoting autophagy to clear harmful protein α-Syn, alleviating symptoms of neurodegenerative diseases like 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 center dot kg(-1)center dot d(-1), i.p.) for 5 days, resulting in a subacute model of PD. PD mice were treated with GM1 ganglioside (25, 50 mg center dot kg(-1)center dot 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 alpha-synuclein (alpha-Syn) A53T-overexpressing PC12 (PC12(alpha-Syn A53T)) cells, treatment with GM1 ganglioside (40 mu M) significantly decreased alpha-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 alpha-Syn as well as GM1-FITC and LC3 in PC12(alpha-Syn A53T)cells. GM1 ganglioside significantly increased the phosphorylation of autophagy regulatory proteins ATG13 and ULK1 in doxycycline-treated PC12(alpha-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 alpha-Syn clearance.
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