期刊
TOXICOLOGY LETTERS
卷 233, 期 2, 页码 163-171出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2014.11.029
关键词
Calcium; GSK3 beta; Parkinson's disease; Rotenone; alpha-Synuclein
类别
资金
- National Natural Science Foundation of China [81274122, 81102831, 81373997, 81173578]
- Special Purpose for New Drug Development [2012ZX09301002-004, 2012ZX09103101-006]
- Studies on Structure and Function of Bioactive Substances from Natural Medicines [IRT1007]
- Beijing Natural Science Foundation [7131013]
- Research Fund for the Doctoral Program of Higher Education of China [20121106130001]
- PUMC Youth Fund
Environmental toxin exposure is associated with the development of Parkinson's disease (PD), and environmental factors can influence the onset of the majority of sporadic PD cases via genetically mediated pathways. Rotenone, a widespread pesticide, induces Parkinsonism and the formation of Lewy bodies in animals; however, the molecular mechanism that underlies a-synuclein aggregation remains unclear. Here, we assessed the aggregation of alpha-synuclein in PC12 cells with or without cross-linking following rotenone exposure via a variety of methods, including western blotting, immunofluorescence and electron microscopy. We demonstrated that rotenone increased the intracellular calcium levels and induced the aggregation and phosphorylation of alpha-synuclein in a calcium-dependent manner. Aggregated alpha-synuclein is typically degraded by autophagy, and rotenone impaired this process. The attenuation of autophagy and alpha-synuclein alterations were reversed by scavenging calcium. Calcium regulates the activity of AKT-glycogen synthase kinase 3 (GSK3)beta. We demonstrated that rotenone attenuated the phosphorylation of AKT and GSK3 beta, and the elimination of calcium reversed these phenomena. As a GSK3 beta inhibitor, lithium promoted autophagy and decreased the aggregation and phosphorylation of alpha-synuclein. GSK3b activation through overexpression depressed autophagy and increased the total protein level and phosphorylation of alpha-synuclein. These results suggest that rotenone-induced alpha-synuclein aggregation is mediated by the calcium/GSK3 beta signaling pathway. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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