The molecular mechanism of rotenone-induced α-synuclein aggregation: emphasizing the role of the calcium/GSK3ß pathway.
Toxicol Lett
; 233(2): 163-71, 2015 Mar 04.
Article
in En
| MEDLINE
| ID: mdl-25433145
ABSTRACT
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 α-synuclein aggregation remains unclear. Here, we assessed the aggregation of α-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 α-synuclein in a calcium-dependent manner. Aggregated α-synuclein is typically degraded by autophagy, and rotenone impaired this process. The attenuation of autophagy and α-synuclein alterations were reversed by scavenging calcium. Calcium regulates the activity of AKT-glycogen synthase kinase 3 (GSK3)ß. We demonstrated that rotenone attenuated the phosphorylation of AKT and GSK3ß, and the elimination of calcium reversed these phenomena. As a GSK3ß inhibitor, lithium promoted autophagy and decreased the aggregation and phosphorylation of α-synuclein. GSK3ß activation through overexpression depressed autophagy and increased the total protein level and phosphorylation of α-synuclein. These results suggest that rotenone-induced α-synuclein aggregation is mediated by the calcium/GSK3ß signaling pathway.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Rotenone
/
Uncoupling Agents
/
Calcium
/
Glycogen Synthase Kinase 3
/
Alpha-Synuclein
/
Insecticides
Limits:
Animals
Language:
En
Journal:
Toxicol Lett
Year:
2015
Document type:
Article