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 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2021年第4期518-528,共11页中国药理学报（英文版）

基　　金：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);the Science and Technology Program of Guangzhou(201903010062).

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 andα-synuclein(α-Syn)A53T-overexpressing PC12(PC12^(α-Syn A53T))cells,treatment with GM1 ganglioside(40μM)significantly decreasedα-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 andα-Syn as well as GM1-FITC and LC3 in PC12^(α-Syn A53T)cells.GM1 ganglioside significantly increased the phosphorylation of autophagy regulatory proteins ATG13 and ULK1 in doxycycline-treated PC12^(α-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-dependentα-Syn clearance.

关 键 词：Parkinson’s disease GM1 ganglioside Α-SYNUCLEIN AUTOPHAGY DOPAMINE 

分 类 号：R749[医药卫生—神经病学与精神病学]