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

• 作者: Yu-Lin Guo Wen-Jun Duan Dan-Hua Lu Xiao-Hui Ma Xiao-Xiao Li Zhao Li Wei Bi Hiroshi Kurihara Hai-Zhi Liu Yi-Fang Li Rong-Rong He
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（4）
• 所属期刊栏目: Article Neuropharmacology
• 页码范围: 518-528
• 页数: 11页
• 语种: 英文

摘要

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.