Acta pharmacologica Sinica, 2021-04, Vol.42 (4), p.518-528
2021
Details
- Autor(en) / Beteiligte
- Titel
- Autophagy-dependent removal of α-synuclein: a novel mechanism of GM1 ganglioside neuroprotection against Parkinson's disease
- Ist Teil von
- Acta pharmacologica Sinica, 2021-04, Vol.42 (4), p.518-528
- Ort / Verlag
- United States: Nature Publishing Group
- Erscheinungsjahr
- 2021
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 ·d , i.p.) for 5 days, resulting in a subacute model of PD. PD mice were treated with GM1 ganglioside (25, 50 mg·kg ·d , 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 (PC12 ) 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 PC12 cells. GM1 ganglioside significantly increased the phosphorylation of autophagy regulatory proteins ATG13 and ULK1 in doxycycline-treated PC12 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1671-4083eISSN: 1745-7254DOI: 10.1038/s41401-020-0454-yTitel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8115090
- Format
- –
- Schlagworte
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, alpha-Synuclein - metabolism, Animals, Autophagy, Autophagy - drug effects, Autophagy-Related Protein-1 Homolog - metabolism, Autophagy-Related Proteins - metabolism, Cell Line, Tumor, Central nervous system, Dopamine, Doxycycline, G(M1) Ganglioside - therapeutic use, Ganglioside GM1, Humans, Intracellular Signaling Peptides and Proteins - metabolism, Male, Metabolites, Mice, Mice, Inbred C57BL, Mitochondria, Movement disorders, MPP, MPTP, Neostriatum, Neurodegenerative diseases, Neuroprotection, Neuroprotection - drug effects, Oxidative stress, Parkinson Disease, Secondary - chemically induced, Parkinson Disease, Secondary - drug therapy, Parkinson's disease, Phagocytosis, Phagosomes, Phosphorylation, Rats, Regulatory proteins, Substantia nigra, Synuclein