title: Mesencephalic astrocyte-derived neurotrophic factor alleviated 6-OHDA-induced cell damage via ROS-AMPK/mTOR mediated autophagic inhibition.
abstract: Autophagy and apoptosis are commonly involved in the dopaminergic neuron damage in the pathogenesis of Parkinson's disease. Recently, the autophagy pathway is thought to be critical to the process of PD. Therefore, the regulation of autophagy may be a potential strategy for PD treatment. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been reported to have neuroprotective effects through anti-apoptosis, anti-oxidative, and anti-inflammatory mechanisms in PD. In this study, we investigated the role of autophagy system in MANF-mediated neuroprotection against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. Our results showed that MANF protected SH-SY5Y cells against 6-OHDA-induced cell viability decrease and apoptosis by inhibiting autophagy. Mitochondrion damage and energetic dysfunction triggered by reactive oxidative stress (ROS) accumulation were also alleviated by MANF treatment. Furthermore, MANF downregulated phosphorylation of AMP-activated protein kinase (AMPK), a cellular energy sensor and regulator, but upregulated phosphorylation of Mammalian target of rapamycin (mTOR) under energy depletion conditions, indicating AMPK/mTOR signaling pathway is involved in the autophagic inhibition of MANF. These results suggest that autophagic inhibition provides protective mechanism of MANF in 6-OHDA-induced SH-SY5Y cell death and this inhibition is associated with AMPK/mTOR pathway.
authors.affiliation: Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, PR China.
authors.forename: Jingxing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, PR China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Biomedical Research Center, Tongji University Suzhou Institute, Building 2,198 Jinfeng Road, Wuzhong District, Suzhou, Jiangsu 215101, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, PR China.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
authors.affiliation: Biomedical Research Center, Tongji University Suzhou Institute, Building 2,198 Jinfeng Road, Wuzhong District, Suzhou, Jiangsu 215101, PR China.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.affiliation: School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, PR China; Biomedical Research Center, Tongji University Suzhou Institute, Building 2,198 Jinfeng Road, Wuzhong District, Suzhou, Jiangsu 215101, PR China. Electronic address: jfang@tongji.edu.cn.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fang
authors.affiliation: Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, PR China. Electronic address: lingjingjin@hotmail.com.
authors.forename: Lingjing
authors.initials: L
authors.lastname: Jin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000187:drug effects*; D006801:Humans; D009414:Nerve Growth Factors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C099695:MANF protein, human; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D016627:Oxidopamine; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: Apoptosis; Autophagy; MANF; ROS; SH-SY5Y cells